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Optimal criteria for the diagnosis of coronary artery disease by dobutamine stress echocardiography
Optimal Criteria for the Diagnosis of Coronary Artery Disease by Dobutamine Stress Echocardiography Abdou Elhendy, MD, PhD, Ron T. van Domburg, MSc, PhD, Jeroen J. Bax, MD, PhD, Don Poldermans, MD, PhD, Peter R. Nierop, MD, PhD, Jaroslaw D. Kasprzak, MD, PhD, and Jos R.T.C. Roelandt, MD, PhD The diagnosis of coronary artery disease (CAD) on the basis of inducible ischemia in >2, rather than >1, segments was suggested to improve specificity of dobutamine stress echocardiography (DSE). However, the impact of using these criteria on the sensitivity and accuracy of DSE was not studied. We studied the accuracy of DSE (up to 40 mg/kg/min) for the diagnosis of CAD in 290 patients with suspected myocardial ischemia using the criteria of >1 and >2 ischemic segments. Ischemia was defined as new or worsening wall motion abnormalities using a 16-segment model. Among the 85 patients without previous myocardial infarction, significant CAD was detected in 51 (60%). Sensitivity, specificity, and accuracy of DSE using >1 ischemic segment were 73%, 85%, and 78%, respectively. Those using >2 segments were 67%, 94%, and 78%, respectively (p 5 NS). Regional specificity improved by using >2 segments (91% vs 96%, p <0.05) at the expense of an equivalent reduction in regional sensitivity (60% vs 44%,
p <0.05), whereas the regional accuracy was similar (80% vs 79% for >1 and >2 segments, respectively). In the 205 patients with previous myocardial infarction, the criterion of ischemia in >1 segment had a higher sensitivity and accuracy for overall diagnosis of CAD (75% vs 64%, p <0.05; 77% vs 68%, p <0.05), infarct-related CAD (64% vs 47%, p <0.005; 70% vs 57%, p <0.01), and remote CAD (74% vs 57%, p <0.005; 78% vs 69%, p <0.05) than the criterion of >2 segments, respectively. It is concluded that in patients without previous myocardial infarction, the use of >2 ischemic segments by DSE for the diagnosis of CAD does not improve the accuracy of DSE compared with the criterion of >1 ischemic segment. Conversely, in patients with previous infarction the use of >2 segments reduces the overall and regional sensitivity and accuracy without a significant improvement in specificity. Q1998 by Excerpta Medica, Inc. (Am J Cardiol 1998;82:1339 –1344)
he noninvasive diagnosis of coronary artery disease (CAD) should be established using a feasible T method with acceptable specificity to avoid a false-
previous myocardial infarction or in certain vascular regions, particularly the posterior circulation. The aim of this study was to find out whether the diagnosis of CAD on the basis of ischemia in $2 myocardial segments improves the overall or regional accuracy of DSE compared with the criterion of ischemia in $1 segment.
positive diagnosis that may lead to subjecting the patient to unneeded coronary angiography. Dobutamine stress echocardiography (DSE) is a clinically useful method for the noninvasive diagnosis of CAD.1–11 However, the reported specificity of the test ranges between 60% and 100%.1–11 The number of ischemic segments required for the diagnosis of CAD by DSE varies in different studies. Some studies used ischemia in $1 myocardial segment4 – 8,12,13 and others used ischemia in $2 segments10,11,14 or in $1 segment, unless the basal inferior or septal wall was involved in which case an adjacent abnormal segment was required.15 It has been suggested that the use of ischemia in $2 segments, rather than $1 segment, improves the specificity of DSE.13,14 However, the impact of this approach on the sensitivity and accuracy of the test is not well known. Additionally, it is not known whether this approach provides a particular advantage in a certain population as in patients with From the Thoraxcenter, University Hospital-Dijkzigt, Erasmus University, Rotterdam, The Netherlands. This study was supported in part by the Department of Cardiology, Cairo University Hospital, Cairo, Egypt and by a grant from the NUFFIC, the Hague, the Netherlands. Manuscript received April 20,1998; revised manuscript received and accepted July 8,1998. Address for reprints: Abdou Elhendy, MD, PhD, Thoraxcenter, Ba 302 Dr Molewaterplein 40,3015 GD Rotterdam, The Netherlands. ©1998 by Excerpta Medica, Inc. All rights reserved.
METHODS
Patient selection: The study population was composed of 290 patients with limited exercise capacity who underwent DSE for evaluation of myocardial ischemia and coronary angiography within 3 months of DSE. The test was not performed in patients with severe heart failure, unstable angina, or severe valvular heart disease. Mean age was 58 6 12 years. There were 202 men and 88 women. Two hundred five patients (71%) had a previous myocardial infarction. Chest pain was the main complaint in 221 patients (76%). Pain was classified as typical anginal pain in 131 patients. Eleven patients (4%) complained of dyspnea, whereas 58 patients (20%) were studied for routine post–myocardial infarction evaluation. Dobutamine stress test: Dobutamine was infused through the antecubital vein starting at a dose of 5 followed by 10 mg/kg/min (3-minute stages), increasing by 10 mg/kg/min every 3 minutes to a maximum of 40 mg/kg/min. Atropine (up to 1 mg) was given in patients not achieving 85% of the predicted maximal 0002-9149/98/$19.00 PII S0002-9149(98)00638-9
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pendent observers without the knowledge of the patients’ clinical or angiographic data. In case of disagreement, a majority decision was achieved by a third investigator. The inter- and intraobserver agreement for dobutamine stress echocardiographic assessment in our laboratory are 91% and 92%, respectively.20 Significant CAD was predicted on the basis of ischemia in $1 segment and the results were compared with those obtained on the basis of ischemia in $2 segments using the 16-segment model. Coronary angiography: Coronary angiography was perFIGURE 1. A diagram illustrating the 16-segment model used to analyze left ventricular func- formed within 3 months of DSE. Lesions were quantified tion and the assignment of each segment to the corresponding coronary artery. The numbers inside the circles represent the code of each segment. The numbers in bold outside the as previously described.21 Sigcircles represent the number of false-positive ischemic responses in the corresponding segnificant CAD was defined as a ments. LAD 5 left anterior descending coronary artery; LCx 5 left circumflex coronary ardiameter stenosis $50% in $1 tery; RCA 5 right coronary artery. major epicardial artery. Coronary arteries were assigned to heart rate and dobutamine infusion was continued. myocardial segments as shown in Figure 1.22 Because The electrocardiogram was monitored throughout do- of the frequent vascular overlap in the posterior and butamine infusion and recorded each minute. Cuff inferior walls, these 2 regions were assigned to both blood pressure was measured at rest, every 3 minutes the left circumflex and the right coronary arteries.4,23 during stress, and at maximal stress. The test was Statistical analysis: Unless specified, data are preinterrupted if severe chest pain, ST-segment depres- sented as mean values 6 SD. The chi-square test was sion .2 mm, significant ventricular or supraventricu- used to compare differences between proportions. The lar arrhythmia, hypertension (blood pressure $240/ Student’s t test was used for analysis of continuous 120 mm Hg), systolic blood pressure decrease .40 data. A p value ,0.05 was considered statistically mm Hg or any intolerable side effect regarded as significant. Sensitivity, specificity, and accuracy were being due to dobutamine occurred during the test. derived according to the standard definitions and were Metoprolol (1 to 5 mg) was administered intrave- represented with 95% confidence intervals (CI). nously to reverse the effects of dobutamine if they did not revert spontaneously and quickly. Ischemia on the electrocardiogram was defined as $0.1 mV horizontal RESULTS Dobutamine stress test: Dobutamine-atropine inor downsloping ST-segment depression 80 ms from the J point compared with baseline level or $0.1 mV duced a significant increase in heart rate (70 6 14 of ST-segment elevation in electrocardiographic leads beats/min at rest to 135 6 18 beats/min at peak stress, corresponding to segments without resting wall mo- p ,0.00001), systolic blood pressure (129 6 23 vs 137 6 27 mm Hg, p ,0.0001), and rate-pressure tion abnormalities.16 Stress echocardiography: Echocardiographic im- product (9,141 6 2,988 to 18,256 6 4,210, ages were acquired from the standard views at rest and p,0.00001). Reasons for test termination were reachduring stress and recovery. The left ventricular wall ing the target heart rate in 207 patients (71%), maxiwas divided into 16 segments as shown in Figure mal dose in 21 patients (7%), angina in 38 patients 1.17,18 Each segment was scored using a 4-point scale, (13%), electrocardiographic changes in 5 patients where 1 5 normal, 2 5 hypokinesia, 3 5 akinesia, (2%), arrhythmias in 5 patients (2%), hypotension in 4 5 dyskinesia. Wall motion score index was derived 11 patients (4%), and chills and anxiety in 3 patients by dividing the sum of the score of the 16 segments by (1%). No study was terminated because of new wall 16. Ischemia was defined as new or worsened wall motion abnormalities. Coronary angiography: Significant CAD was demotion abnormalities. As we have previously concluded, ischemia was not considered if akinetic seg- tected in 221 patients (76%). Eighty-five patients ments at rest became dyskinetic during stress.19 The (29%) had 1-vessel disease, 72 (25%) had 2-vessel echocardiograms were recorded on videotapes and disease, and 64 (22%) had 3-vessel disease. Normal digitized on optical disk (Vingmed-CFM 800, Ving- coronary arteries or ,50% lesions were present in 69 med Sound A/S, Horten, Norway). Images were com- patients (24%). Patients with previous myocardial inpared side by side in quad-screen format by 2 inde- farction had a higher prevalence of significant CAD 1340 THE AMERICAN JOURNAL OF CARDIOLOGYT
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TABLE I Accuracy of Ischemic Pattern at Dobutamine Stress Echocardiography for the Diagnosis of Significant CAD in Patients Without Previous Myocardial Infarction Using $1 and $2 Ischemic Segments $1 Segment Overall diagnosis Sensitivity Specificity Accuracy Sensitivity in 1-vessel CAD Sensitivity in 2-vessel CAD Sensitivity in 3-vessel CAD Multivessel ischemic pattern Sensitivity Specificity Accuracy
73% 85% 78% 60% 78% 100%
(37/51) (29/34) (66/85) (18/30) (7/9) (12/12)
52% (11/21) 94% (60/64) 84% (71/85)
CI 63–82 78–93 69–87 48–72 65–90 100–100 42–63 89–99 76–92
$2 Segments 67% 94% 78% 50% 78% 100%
CI
(34/51) (32/34) (66/85) (15/30) (7/9) 12/12
57–77 89–99 69–87 38–62 65–90 100–100
38% (8/21) 98% (63/64) 84% (71/85)
28–48 96–101 76–92
Numbers in parentheses are numbers of patients. CI 5 95% confidence interval.
Left anterior descending Sensitivity Specificity Accuracy Left circumflex Sensitivity Specificity Accuracy Right Sensitivity Specificity Accuracy All arteries Sensitivity Specificity Accuracy
$1 Segment
Comparison of echocardiography and electrocardiography: Among 258
patients with interpretable baseline electrocardiograms, ischemic electrocardiographic changes occurred in 72 of 196 patients with and in 10 of 62 patients without CAD (sensitivity 37% [CI 31 to 43], specificity 84% [CI 79 to 88], and accuracy 48% [CI 42 to 54]). DSE was more sensitive and accurate than electrocardiography using $1 or $2 ischemic segments (p ,0.0000001 for all).
Prevalence of false-positive results in different myocardial segments:
TABLE II Accuracy of Ischemic Pattern at Dobutamine Stress Echocardiography for the Diagnosis of Individual CAD in Patients Without Previous Myocardial Infarction Using $1 and $2 Ischemic Segments Coronary Artery
vascular territories (Table III), and for the diagnosis of individual CAD (Table IV).
$2 Segments
CI
CI
61% (22/36) 90% (44/49) 78% (66/85)
51–71 83–96 69–87
50% (18/36) 96% (47/49) 76% (65/85)
39–61 92–100 67–86
55% (12/22) 90% (57/63) 81% (69/85)
44–65 84–97 73–90
36% (8/22) 95% (60/63) 80% (68/85)
26–47 91–100 71–89
There was no significant difference between the 16 segments with regard to the positive predictive value of an ischemic pattern in each segment for the diagnosis of significant stenosis of the related coronary artery (Figure 2). The distribution of false-positive ischemic segments is shown in Figure 1.
DISCUSSION
There is no agreement between previous studies of DSE with regard to the number of ischemic segments 62% (16/26) 51–72 42% (11/26) 32–53 92% (54/59) 85–98 94% (58/59) 88–99 required for the diagnosis of CAD. 82% (70/85) 74–91 78% (69/85) 70–87 Although it is well understood that the use of $2, rather than $1, isch60% (50/84) 53–66 44% (37/84)* 38–50 emic segment would improve the 91% (155/171) 87–94 96% (165/171)* 94–99 specificity of DSE,13 the extent to 80% (205/255) 76–85 79% (202/255) 74–84 which the use of this criterion may *p ,0.05. decrease sensitivity and accuracy is Numbers in parentheses are numbers of patients. not well studied. Our study shows Abbreviation as in Table I. that in patients without previous myocardial infarction, the use of $2 ischemic segments was associated than patients without previous myocardial infarction with a modest improvement in specificity and an (83% vs 60%, p ,0.0001). equivalent modest decrease in sensitivity, whereas the Stress echocardiography: Wall motion score index overall and regional accuracy was similar when comincreased significantly from rest to peak stress (1.53 6 pared witih the criterion of $1 ischemic segment. 0.46 vs 1.75 6 0.52, p ,0.0005). In patients without Conversely, in patients with previous myocardial inmyocardial infarction the use of $2 ischemic seg- farction, the use of $2 segments resulted in a signifments resulted in a slight improvement in specificity icant reduction in sensitivity and accuracy without a and an equivalent slight decrease in sensitivity; significant improvement in specificity when compared whereas the accuracy was fairly similar to that ob- with the criterion of ischemia in $1 segment. This tained by using ischemia in $1 segment for the over- difference was observed in the overall and regional all (Table I) and regional diagnosis (Table II) of diagnosis of significant CAD, infarct-related, and resignificant CAD. In patients with previous myocardial mote CAD, and the diagnosis of multivessel disease infarction the use of $2 segments resulted in a sig- on the basis of inducible ischemia in $2 vascular nificant reduction in sensitivity and accuracy without a territories. The use of $2 ischemic segments for the significant improvement in specificity when compared diagnosis of CAD did not provide improvement of with the criterion of ischemia in $1 segment. This accuracy in any vascular region. This is because we difference was observed in the overall diagnosis of did not find a false-positive ischemic response to significant CAD, infarct-related and remote CAD, involve a particular segment or vascular region. In our multivessel CAD on the basis of ischemia in $2 laboratory, we do not consider new wall motion abCORONARY ARTERY DISEASE/OPTIMAL DIAGNOSTIC CRITERIA FOR DSE
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TABLE III Accuracy of Ischemic Pattern at Dobutamine Stress Echocardiography for the Diagnosis of Significant CAD in Patients With Previous Myocardial Infarction Using $1 and $2 Ischemic Segments Diagnostic Parameters Overall diagnosis Sensitivity Specificity Accuracy Sensitivity in 1-vessel CAD Sensitivity in 2-vessel CAD Sensitivity in 3-vessel CAD Multivessel ischemic pattern Sensitivity Specificity Accuracy Infarct-related artery Sensitivity Specificity Accuracy Remote coronary artery Sensitivity Specificity Accuracy
$1 Segment 75% 86% 77% 60% 79% 85%
CI
$2 Segments
CI
p Value
(127/170) (30/35) (157/205) (33/55) (50/63) (44/52)
69–81 81–91 71–83 50–70 71–87 77–92
64% 86% 68% 42% 68% 83%
(109/170) (30/35) (139/205) (23/55) (43/63) (43/52)
57–71 81–91 61–74 32–52 59–78 75–91
0.03 1 0.045 0.057 0.15 0.8
55% (63/115) 90% (81/90) 70% (144/205)
48–62 86–94 64–77
37% (42/115) 92% (83/90) 61% (125/205)
30–43 88–96 54–68
0.006 0.8 0.048
64% (101/158) 89% (42/47) 70% (143/205)
57–71 85–94 63–76
47% (74/158) 91% (43/47) 57% (117/205)
40–54 88–95 50–64
0.002 0.7 0.008
74% (91/123) 84% (69/82) 78% (160/205)
68–80 79–89 72–84
57% (70/123) 88% (72/82) 69% (142/205)
50–64 83–92 63–76
0.0048 0.5 0.043
Numbers in parentheses are numbers of patients. Abbreviations as in Table I.
TABLE IV Accuracy of Ischemic Pattern at Dobutamine Stress Echocardiography for the Diagnosis of Individual CAD in Patients With Previous Myocardial Infarction Using $1 and $2 Ischemic Segments Coronary Artery Left anterior descending Sensitivity Specificity Accuracy Left Sensitivity Specificity Accuracy Right Sensitivity Specificity Accuracy All arteries Sensitivity Specificity Accurac
$1 Segment
CI
$2 Segments
CI
67% (76/113) 83% (76/92) 74% (152/205)
61–74 77–88 68–80
53% (60/113) 85% (78/92) 67% (138/205)
46–60 80–90 61–74
0.03 0.7 0.1
63% (63/100) 87% (91/105) 75% (154/205)
56–70 82–91 69–81
43% (43/100) 90% (95/105) 67% (138/205)
36–50 86–95 61–74
0.0046 0.4 0.04
65% (81/124) 89% (72/81) 75% (153/205)
59–72 85–93 68–81
40% (50/124) 92% (75/81) 59% (125/205)
33–47 88–96 52–66
0.00008 0.4 0.003
65% (220/337) 86% (239/278) 75% (459/615)
61–69 83–89 71–78
45% (153/337) 89% (248/278) 65% (401/615)
41–49 87–92 61–69
0.0000002 0.2 0.0003
p Value
Numbers in parentheses are numbers of patients. Abbreviation as in Table I.
normalities as an end point for the test unless they are very extensive and accompanied by left ventricular dilatation. In this study, the test was not terminated in any patient because of this reason, and therefore the diagnostic accuracy of DSE using $2 ischemic segments as well as the detection of multivessel CAD on the basis of inducible ischemia in $2 vascular regions could be studied. The different results between patients with and without myocardial infarction may be explained by the higher prevalence of significant CAD, multivessel CAD, and myocardial ischemia in patients with than without myocardial infarction. Consequently, the group with myocardial infarction was more vulnerable for a reduced sensitivity without significant improvement in specificity when the strict criterion of $2 1342 THE AMERICAN JOURNAL OF CARDIOLOGYT
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segments was used. Another explanation is the presence of wall motion abnormalities at rest in patients with myocardial infarction. The presence of extensive dyssynergy would limit the number of myocardial segments in which ischemia may be elicited. Although we have previously shown that regional sensitivity of DSE is enhanced in myocardial regions with mild and moderate resting wall motion abnormalities,4 the diagnosis of ischemia in that study was considered in $1 segment. Therefore the use of more strict criterion of $2 segments would markedly reduce sensitivity because of the frequent occurrence of ischemia limited to 1 segment. However, this theory fails to explain the significant reduction in sensitivity in myocardial regions remote from the infarct zone when criterion of ischemia in $2 segments was used. The frequent DECEMBER 1, 1998
FIGURE 2. The positive predictive value of ischemic pattern in each of the 16 segments for the diagnosis of significant stenosis of the related coronary artery. Code numbers of the segments are the same as shown in Figure 1.
occurrence of ischemia confined to 1 segment remote from the infarct region may be due to a different threshold for ischemia between the infarct-related and remote regions. Periinfarction ischemia may occur concomitantly with the possibility of reaching an end point (angina, electrocardiographic changes, or maximal dose) before ischemia becomes more extensive.4 Comparison with previous studies: Bach et al13 studied 39 patients with a false-positive DSE among 342 studies. They found that false-positive findings tended to involve small wall motion abnormalities that are frequently located in basal segments of the posterior myocardial circulation.13 When these investigators limited the diagnosis of CAD in the posterior circulation to wall motion abnormalities that involve at least 2 myocardial segments or those that involve more than only basal segments, the incidence of false-positive studies decreased by 25.5% and 30.8%, respectively. However, the sensitivity and specificity of DSE using criteria of abnormalities in $1 or $2 segments were not assessed. Latcham et al12 reported 7 false-positive DSE studies among 89 patients who underwent coronary angiography. They concluded that false-positive DSE often involves the inferobasal and midposterobasal left ventricular segments and that recognition of this pattern increased DSE specificity and could decrease test sensitivity. In our study, we did not find a difference in the specificity of DSE in the 3 vascular regions despite the use of $1 segment to define an abnormal test. Additionally, the positive predictive value of an ischemic pattern in each of the 16 myocardial segments for the diagnosis of significant stenosis of the related artery was not different. This approach is more relevant than reporting the number of false-positive responses in each segment because this number may be influenced by the prevalence of the disease in the related artery and the frequency of the occurrence of an ischemic response in a particular segment, which may yield different results in different patient populations.
Study limitations: Most of the study patients (76%) had significant CAD. This may tend to accentuate the reduction in sensitivity and dampen the improvement in specificity when ischemia is considered in $2, rather than $1, myocardial segment. However, even in patients without previous myocardial infarction, the criterion of ischemia in $2 segments failed to improve the accuracy despite the fact that the prevalence of CAD was only 60% in these patients. These results represent the experience of our center and will depend in part on how conservative the reviewers are in scoring ischemia and their recognition of the normal pattern of myocardial thickening and wall motion in different myocardial regions, particularly the basal segments of the posterior circulation which have been implicated in false-positive studies by some investigators.12,13 Therefore, further studies are needed to confirm our results.
1. Geleijnse ML, Fioretti PM, Roelandt JRTC. Methodology, feasibility safety
and diagnostic accuracy of dobutamine stress echocardiography. J Am Coll Cardiol 1997;30:595– 606. 2. Marcovitz PA, Armstrong WF. Accuracy of dobutamine stress echocardiography in detecting coronary artery disease. Am J Cardiol 1992;69:1269 –1273. 3. Marwick TH, D’Hondt AM, Baudhuin T, Willemat A, Wijns W, Detry J, Melin J. Optimal use of dobutamine stress for the detection and evaluation of coronary artery disease: combination with echocardiography, scintigraphy or both? J Am Coll Cardiol 1993;22:159 –167. 4. Elhendy A, van Domburg RT, Roelandt JRTC, Geleijnse ML, Cornel JH, El-Said GM, Fioretti PM. Accuracy of dobutamine stress echocardiography for the diagnosis of coronary artery stenosis in patients with myocardial infarction: the impact of extent and severity of left ventricular dysfunction. Heart 1996;76: 123–128. 5. Elhendy A, Geleijnse ML, Roelandt JRTC, van Domburg RT, TenCate FJ, Nierop PR, Bax JJ, El-Refaee M, Ibrahim M, El-Said GM, Fioretti PM. Comparison of dobutamine stress echocardiography and 99m-technetium sestamibi SPECT myocardial perfusion scintigraphy in predicting the extent of coronary artery disease in patients with healed myocardial infarction. Am J Cardiol 1997;79:7–12. 6. Elhendy A, Geleijnse ML, Roelandt JRTC, Cornel JH, van Domburg RT, El-Refaee M, Ibrahim MM, El-Said GM, Fioretti PM. Assessment of patients after coronary artery bypass grafting by dobutamine stress echocardiography. Am J Cardiol 1996;77:1234 –1236. 7. Salustri A, Fioretti PM, McNeill AJ, Pozzoli MMA, Roelandt JRTC. Pharmacological stress echocardiography in the diagnosis of coronary artery disease and
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myocardial ischemia: a comparison between dobutamine and dipyridamole. Eur Heart J 1992;13:1356 –1362. 8. Forster T, McNeill AJ, Salustri A, Reijs AEM, El-Said EM, Roelandt JRTC, Fioretti PM. Simultaneous dobutamine stress echocardiography and 99m-technetium isonitrile single-photon emission computed tomography in patients with suspected coronary artery disease. J Am Coll Cardiol 1993;21:1591–1596. 9. Previtali M, Lanzarini L, Ferrario M, Tortorici M, Mussini A, Montemartini C. Dobutamine versus dipyridamole in coronary artery disease. Circulation 1991; (suppl III):III-27–III-31. 10. Martin TW, Seaworth JF, Johns JP, Pupa LE, Condos WR. Comparison of adenosine, dipyridamole, and dobutamine in stress echocardiography. Ann Intern Med 1992;116:190 –196. 11. Schroder K, Voller H, Dingerkus H, Munzberg H, Dissmann R, Linderer T, Schultheiss H. Comparison of the diagnostic potential of four echocardiographic stress tests shortly after acute myocardial infarction: submaximal exercise, transesophageal atrial pacing, dipyridamole, and dobutamine-atropine. Am J Cardiol 1996;77:909 –914. 12. Latcham AP, Orsinelli DA, Pearson AC. Recognition of the segmental tendency of false-positive dobutamine stress echocardiography and its effects on test sensitivity and specificity. Am Heart J 1995;129:1047–1050. 13. Bach D, Muller DWM, Gros BJ, Armstrong WF. False positive dobutamine stress echocardiograms: characterization of clinical, echocardiographic and angiographic findings. J Am Coll Cardiol 1994;24:928 –933. 14. Smart SC, Knickelbine T, Stoiber TR, Carlos M, Wynsen JC, Sagar KB. Safety and accuracy of dobutamine-atropine stress echocardiograhy for the detection of residual stenosis of infarct-related artery and multivessel disease during the first year after acute myocardial infarction. Circulation 1997;95:1394 –1401. 15. Secknus M, Marwick TH. Evolution of dobutamine echocardiography protocols and indications: safety and side effects in 3011 studies over 5 years. J Am Coll Cardiol 1997;29:1234 –1240.
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16. Elhendy A, Geleijnse ML, Roelandt JRTC, van Domburg RT, Cornel JH, TenCate FJ, Postma-Tjoa J, Reijs AEM, El-Said GM, Fioretti PM. Evaluation by quantitative 99m-technetium MIBI SPECT and echocardiography of myocardial perfusion and wall motion abnormalities in patients with dobutamine-induced ST-segment elevation. Am J Cardiol 1995;76:441– 448. 17. Bourdillon PDV, Broderik TM, Sawada SG, Armstrong WF, Ryan T, Dillon JC, Fineberg NS, Feigenbaum H. Regional wall motion index for infarct and non-infarct region after reperfusion in acute myocardial infarction: comparison with global wall motion index. J Am Soc Echocardiogr 1989;2:398 – 407. 18. American Society of Echocardiography Committee on Standards. Subcommitte on Quantitation of Two-Dimensional Echocardiograms. Recommendations of quantification of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;2:358 –367. 19. Elhendy A, Cornel JH, Roelandt JRTC, van Domburg RT, Nierop PR, El-Said GM, Fioretti PM. Relation between contractile response of akinetic segments during dobutamine stress echocardiography and ischemia assessed by simultaneous 201 thallium SPECT. Am J Cardiol 1996;77:955–959. 20. Bellotti P, Fioretti PM, Forster T, McNeill AJ, El-Said EM, Salustri A, Roelandt JRTC. Reproducibility of the dobutamine-atropine echocardiography stress test. Echocardiography 1993;10:93–97. 21. Baptista J, Arnese M, Roelandt JRTC, Fioretti P, Keane D, Escaned J, Boersma E, DiMario C, Serruys PW. Quantitative coronary angiography in the estimation of the functional significance of coronary stenosis: correlation with dobutamine-atropine stress test. J Am Coll Cardiol 1994;23:1434 –1439. 22. Segar DS, Brown SE, Sawada SG, Ryan T, Feigenbaum H. Dobutamine stress echocardiography: correlation with coronary lesion severity as determined by quantitative angiography. J Am Coll Cardiol 1992;19:1197–1202. 23. Armstrong WF, O’Donnell J, Rayan T, Feigenbaum H. Effect of prior myocardial infarction and extent and location of coronary artery disease on accuracy of exercise echocardiography. J Am Coll Cardiol 1987;10:531–538.
DECEMBER 1, 1998
p <0.05), whereas the regional accuracy was similar (80% vs 79% for >1 and >2 segments, respectively). In the 205 patients with previous myocardial infarction, the criterion of ischemia in >1 segment had a higher sensitivity and accuracy for overall diagnosis of CAD (75% vs 64%, p <0.05; 77% vs 68%, p <0.05), infarct-related CAD (64% vs 47%, p <0.005; 70% vs 57%, p <0.01), and remote CAD (74% vs 57%, p <0.005; 78% vs 69%, p <0.05) than the criterion of >2 segments, respectively. It is concluded that in patients without previous myocardial infarction, the use of >2 ischemic segments by DSE for the diagnosis of CAD does not improve the accuracy of DSE compared with the criterion of >1 ischemic segment. Conversely, in patients with previous infarction the use of >2 segments reduces the overall and regional sensitivity and accuracy without a significant improvement in specificity. Q1998 by Excerpta Medica, Inc. (Am J Cardiol 1998;82:1339 –1344)
he noninvasive diagnosis of coronary artery disease (CAD) should be established using a feasible T method with acceptable specificity to avoid a false-
previous myocardial infarction or in certain vascular regions, particularly the posterior circulation. The aim of this study was to find out whether the diagnosis of CAD on the basis of ischemia in $2 myocardial segments improves the overall or regional accuracy of DSE compared with the criterion of ischemia in $1 segment.
positive diagnosis that may lead to subjecting the patient to unneeded coronary angiography. Dobutamine stress echocardiography (DSE) is a clinically useful method for the noninvasive diagnosis of CAD.1–11 However, the reported specificity of the test ranges between 60% and 100%.1–11 The number of ischemic segments required for the diagnosis of CAD by DSE varies in different studies. Some studies used ischemia in $1 myocardial segment4 – 8,12,13 and others used ischemia in $2 segments10,11,14 or in $1 segment, unless the basal inferior or septal wall was involved in which case an adjacent abnormal segment was required.15 It has been suggested that the use of ischemia in $2 segments, rather than $1 segment, improves the specificity of DSE.13,14 However, the impact of this approach on the sensitivity and accuracy of the test is not well known. Additionally, it is not known whether this approach provides a particular advantage in a certain population as in patients with From the Thoraxcenter, University Hospital-Dijkzigt, Erasmus University, Rotterdam, The Netherlands. This study was supported in part by the Department of Cardiology, Cairo University Hospital, Cairo, Egypt and by a grant from the NUFFIC, the Hague, the Netherlands. Manuscript received April 20,1998; revised manuscript received and accepted July 8,1998. Address for reprints: Abdou Elhendy, MD, PhD, Thoraxcenter, Ba 302 Dr Molewaterplein 40,3015 GD Rotterdam, The Netherlands. ©1998 by Excerpta Medica, Inc. All rights reserved.
METHODS
Patient selection: The study population was composed of 290 patients with limited exercise capacity who underwent DSE for evaluation of myocardial ischemia and coronary angiography within 3 months of DSE. The test was not performed in patients with severe heart failure, unstable angina, or severe valvular heart disease. Mean age was 58 6 12 years. There were 202 men and 88 women. Two hundred five patients (71%) had a previous myocardial infarction. Chest pain was the main complaint in 221 patients (76%). Pain was classified as typical anginal pain in 131 patients. Eleven patients (4%) complained of dyspnea, whereas 58 patients (20%) were studied for routine post–myocardial infarction evaluation. Dobutamine stress test: Dobutamine was infused through the antecubital vein starting at a dose of 5 followed by 10 mg/kg/min (3-minute stages), increasing by 10 mg/kg/min every 3 minutes to a maximum of 40 mg/kg/min. Atropine (up to 1 mg) was given in patients not achieving 85% of the predicted maximal 0002-9149/98/$19.00 PII S0002-9149(98)00638-9
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pendent observers without the knowledge of the patients’ clinical or angiographic data. In case of disagreement, a majority decision was achieved by a third investigator. The inter- and intraobserver agreement for dobutamine stress echocardiographic assessment in our laboratory are 91% and 92%, respectively.20 Significant CAD was predicted on the basis of ischemia in $1 segment and the results were compared with those obtained on the basis of ischemia in $2 segments using the 16-segment model. Coronary angiography: Coronary angiography was perFIGURE 1. A diagram illustrating the 16-segment model used to analyze left ventricular func- formed within 3 months of DSE. Lesions were quantified tion and the assignment of each segment to the corresponding coronary artery. The numbers inside the circles represent the code of each segment. The numbers in bold outside the as previously described.21 Sigcircles represent the number of false-positive ischemic responses in the corresponding segnificant CAD was defined as a ments. LAD 5 left anterior descending coronary artery; LCx 5 left circumflex coronary ardiameter stenosis $50% in $1 tery; RCA 5 right coronary artery. major epicardial artery. Coronary arteries were assigned to heart rate and dobutamine infusion was continued. myocardial segments as shown in Figure 1.22 Because The electrocardiogram was monitored throughout do- of the frequent vascular overlap in the posterior and butamine infusion and recorded each minute. Cuff inferior walls, these 2 regions were assigned to both blood pressure was measured at rest, every 3 minutes the left circumflex and the right coronary arteries.4,23 during stress, and at maximal stress. The test was Statistical analysis: Unless specified, data are preinterrupted if severe chest pain, ST-segment depres- sented as mean values 6 SD. The chi-square test was sion .2 mm, significant ventricular or supraventricu- used to compare differences between proportions. The lar arrhythmia, hypertension (blood pressure $240/ Student’s t test was used for analysis of continuous 120 mm Hg), systolic blood pressure decrease .40 data. A p value ,0.05 was considered statistically mm Hg or any intolerable side effect regarded as significant. Sensitivity, specificity, and accuracy were being due to dobutamine occurred during the test. derived according to the standard definitions and were Metoprolol (1 to 5 mg) was administered intrave- represented with 95% confidence intervals (CI). nously to reverse the effects of dobutamine if they did not revert spontaneously and quickly. Ischemia on the electrocardiogram was defined as $0.1 mV horizontal RESULTS Dobutamine stress test: Dobutamine-atropine inor downsloping ST-segment depression 80 ms from the J point compared with baseline level or $0.1 mV duced a significant increase in heart rate (70 6 14 of ST-segment elevation in electrocardiographic leads beats/min at rest to 135 6 18 beats/min at peak stress, corresponding to segments without resting wall mo- p ,0.00001), systolic blood pressure (129 6 23 vs 137 6 27 mm Hg, p ,0.0001), and rate-pressure tion abnormalities.16 Stress echocardiography: Echocardiographic im- product (9,141 6 2,988 to 18,256 6 4,210, ages were acquired from the standard views at rest and p,0.00001). Reasons for test termination were reachduring stress and recovery. The left ventricular wall ing the target heart rate in 207 patients (71%), maxiwas divided into 16 segments as shown in Figure mal dose in 21 patients (7%), angina in 38 patients 1.17,18 Each segment was scored using a 4-point scale, (13%), electrocardiographic changes in 5 patients where 1 5 normal, 2 5 hypokinesia, 3 5 akinesia, (2%), arrhythmias in 5 patients (2%), hypotension in 4 5 dyskinesia. Wall motion score index was derived 11 patients (4%), and chills and anxiety in 3 patients by dividing the sum of the score of the 16 segments by (1%). No study was terminated because of new wall 16. Ischemia was defined as new or worsened wall motion abnormalities. Coronary angiography: Significant CAD was demotion abnormalities. As we have previously concluded, ischemia was not considered if akinetic seg- tected in 221 patients (76%). Eighty-five patients ments at rest became dyskinetic during stress.19 The (29%) had 1-vessel disease, 72 (25%) had 2-vessel echocardiograms were recorded on videotapes and disease, and 64 (22%) had 3-vessel disease. Normal digitized on optical disk (Vingmed-CFM 800, Ving- coronary arteries or ,50% lesions were present in 69 med Sound A/S, Horten, Norway). Images were com- patients (24%). Patients with previous myocardial inpared side by side in quad-screen format by 2 inde- farction had a higher prevalence of significant CAD 1340 THE AMERICAN JOURNAL OF CARDIOLOGYT
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TABLE I Accuracy of Ischemic Pattern at Dobutamine Stress Echocardiography for the Diagnosis of Significant CAD in Patients Without Previous Myocardial Infarction Using $1 and $2 Ischemic Segments $1 Segment Overall diagnosis Sensitivity Specificity Accuracy Sensitivity in 1-vessel CAD Sensitivity in 2-vessel CAD Sensitivity in 3-vessel CAD Multivessel ischemic pattern Sensitivity Specificity Accuracy
73% 85% 78% 60% 78% 100%
(37/51) (29/34) (66/85) (18/30) (7/9) (12/12)
52% (11/21) 94% (60/64) 84% (71/85)
CI 63–82 78–93 69–87 48–72 65–90 100–100 42–63 89–99 76–92
$2 Segments 67% 94% 78% 50% 78% 100%
CI
(34/51) (32/34) (66/85) (15/30) (7/9) 12/12
57–77 89–99 69–87 38–62 65–90 100–100
38% (8/21) 98% (63/64) 84% (71/85)
28–48 96–101 76–92
Numbers in parentheses are numbers of patients. CI 5 95% confidence interval.
Left anterior descending Sensitivity Specificity Accuracy Left circumflex Sensitivity Specificity Accuracy Right Sensitivity Specificity Accuracy All arteries Sensitivity Specificity Accuracy
$1 Segment
Comparison of echocardiography and electrocardiography: Among 258
patients with interpretable baseline electrocardiograms, ischemic electrocardiographic changes occurred in 72 of 196 patients with and in 10 of 62 patients without CAD (sensitivity 37% [CI 31 to 43], specificity 84% [CI 79 to 88], and accuracy 48% [CI 42 to 54]). DSE was more sensitive and accurate than electrocardiography using $1 or $2 ischemic segments (p ,0.0000001 for all).
Prevalence of false-positive results in different myocardial segments:
TABLE II Accuracy of Ischemic Pattern at Dobutamine Stress Echocardiography for the Diagnosis of Individual CAD in Patients Without Previous Myocardial Infarction Using $1 and $2 Ischemic Segments Coronary Artery
vascular territories (Table III), and for the diagnosis of individual CAD (Table IV).
$2 Segments
CI
CI
61% (22/36) 90% (44/49) 78% (66/85)
51–71 83–96 69–87
50% (18/36) 96% (47/49) 76% (65/85)
39–61 92–100 67–86
55% (12/22) 90% (57/63) 81% (69/85)
44–65 84–97 73–90
36% (8/22) 95% (60/63) 80% (68/85)
26–47 91–100 71–89
There was no significant difference between the 16 segments with regard to the positive predictive value of an ischemic pattern in each segment for the diagnosis of significant stenosis of the related coronary artery (Figure 2). The distribution of false-positive ischemic segments is shown in Figure 1.
DISCUSSION
There is no agreement between previous studies of DSE with regard to the number of ischemic segments 62% (16/26) 51–72 42% (11/26) 32–53 92% (54/59) 85–98 94% (58/59) 88–99 required for the diagnosis of CAD. 82% (70/85) 74–91 78% (69/85) 70–87 Although it is well understood that the use of $2, rather than $1, isch60% (50/84) 53–66 44% (37/84)* 38–50 emic segment would improve the 91% (155/171) 87–94 96% (165/171)* 94–99 specificity of DSE,13 the extent to 80% (205/255) 76–85 79% (202/255) 74–84 which the use of this criterion may *p ,0.05. decrease sensitivity and accuracy is Numbers in parentheses are numbers of patients. not well studied. Our study shows Abbreviation as in Table I. that in patients without previous myocardial infarction, the use of $2 ischemic segments was associated than patients without previous myocardial infarction with a modest improvement in specificity and an (83% vs 60%, p ,0.0001). equivalent modest decrease in sensitivity, whereas the Stress echocardiography: Wall motion score index overall and regional accuracy was similar when comincreased significantly from rest to peak stress (1.53 6 pared witih the criterion of $1 ischemic segment. 0.46 vs 1.75 6 0.52, p ,0.0005). In patients without Conversely, in patients with previous myocardial inmyocardial infarction the use of $2 ischemic seg- farction, the use of $2 segments resulted in a signifments resulted in a slight improvement in specificity icant reduction in sensitivity and accuracy without a and an equivalent slight decrease in sensitivity; significant improvement in specificity when compared whereas the accuracy was fairly similar to that ob- with the criterion of ischemia in $1 segment. This tained by using ischemia in $1 segment for the over- difference was observed in the overall and regional all (Table I) and regional diagnosis (Table II) of diagnosis of significant CAD, infarct-related, and resignificant CAD. In patients with previous myocardial mote CAD, and the diagnosis of multivessel disease infarction the use of $2 segments resulted in a sig- on the basis of inducible ischemia in $2 vascular nificant reduction in sensitivity and accuracy without a territories. The use of $2 ischemic segments for the significant improvement in specificity when compared diagnosis of CAD did not provide improvement of with the criterion of ischemia in $1 segment. This accuracy in any vascular region. This is because we difference was observed in the overall diagnosis of did not find a false-positive ischemic response to significant CAD, infarct-related and remote CAD, involve a particular segment or vascular region. In our multivessel CAD on the basis of ischemia in $2 laboratory, we do not consider new wall motion abCORONARY ARTERY DISEASE/OPTIMAL DIAGNOSTIC CRITERIA FOR DSE
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TABLE III Accuracy of Ischemic Pattern at Dobutamine Stress Echocardiography for the Diagnosis of Significant CAD in Patients With Previous Myocardial Infarction Using $1 and $2 Ischemic Segments Diagnostic Parameters Overall diagnosis Sensitivity Specificity Accuracy Sensitivity in 1-vessel CAD Sensitivity in 2-vessel CAD Sensitivity in 3-vessel CAD Multivessel ischemic pattern Sensitivity Specificity Accuracy Infarct-related artery Sensitivity Specificity Accuracy Remote coronary artery Sensitivity Specificity Accuracy
$1 Segment 75% 86% 77% 60% 79% 85%
CI
$2 Segments
CI
p Value
(127/170) (30/35) (157/205) (33/55) (50/63) (44/52)
69–81 81–91 71–83 50–70 71–87 77–92
64% 86% 68% 42% 68% 83%
(109/170) (30/35) (139/205) (23/55) (43/63) (43/52)
57–71 81–91 61–74 32–52 59–78 75–91
0.03 1 0.045 0.057 0.15 0.8
55% (63/115) 90% (81/90) 70% (144/205)
48–62 86–94 64–77
37% (42/115) 92% (83/90) 61% (125/205)
30–43 88–96 54–68
0.006 0.8 0.048
64% (101/158) 89% (42/47) 70% (143/205)
57–71 85–94 63–76
47% (74/158) 91% (43/47) 57% (117/205)
40–54 88–95 50–64
0.002 0.7 0.008
74% (91/123) 84% (69/82) 78% (160/205)
68–80 79–89 72–84
57% (70/123) 88% (72/82) 69% (142/205)
50–64 83–92 63–76
0.0048 0.5 0.043
Numbers in parentheses are numbers of patients. Abbreviations as in Table I.
TABLE IV Accuracy of Ischemic Pattern at Dobutamine Stress Echocardiography for the Diagnosis of Individual CAD in Patients With Previous Myocardial Infarction Using $1 and $2 Ischemic Segments Coronary Artery Left anterior descending Sensitivity Specificity Accuracy Left Sensitivity Specificity Accuracy Right Sensitivity Specificity Accuracy All arteries Sensitivity Specificity Accurac
$1 Segment
CI
$2 Segments
CI
67% (76/113) 83% (76/92) 74% (152/205)
61–74 77–88 68–80
53% (60/113) 85% (78/92) 67% (138/205)
46–60 80–90 61–74
0.03 0.7 0.1
63% (63/100) 87% (91/105) 75% (154/205)
56–70 82–91 69–81
43% (43/100) 90% (95/105) 67% (138/205)
36–50 86–95 61–74
0.0046 0.4 0.04
65% (81/124) 89% (72/81) 75% (153/205)
59–72 85–93 68–81
40% (50/124) 92% (75/81) 59% (125/205)
33–47 88–96 52–66
0.00008 0.4 0.003
65% (220/337) 86% (239/278) 75% (459/615)
61–69 83–89 71–78
45% (153/337) 89% (248/278) 65% (401/615)
41–49 87–92 61–69
0.0000002 0.2 0.0003
p Value
Numbers in parentheses are numbers of patients. Abbreviation as in Table I.
normalities as an end point for the test unless they are very extensive and accompanied by left ventricular dilatation. In this study, the test was not terminated in any patient because of this reason, and therefore the diagnostic accuracy of DSE using $2 ischemic segments as well as the detection of multivessel CAD on the basis of inducible ischemia in $2 vascular regions could be studied. The different results between patients with and without myocardial infarction may be explained by the higher prevalence of significant CAD, multivessel CAD, and myocardial ischemia in patients with than without myocardial infarction. Consequently, the group with myocardial infarction was more vulnerable for a reduced sensitivity without significant improvement in specificity when the strict criterion of $2 1342 THE AMERICAN JOURNAL OF CARDIOLOGYT
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segments was used. Another explanation is the presence of wall motion abnormalities at rest in patients with myocardial infarction. The presence of extensive dyssynergy would limit the number of myocardial segments in which ischemia may be elicited. Although we have previously shown that regional sensitivity of DSE is enhanced in myocardial regions with mild and moderate resting wall motion abnormalities,4 the diagnosis of ischemia in that study was considered in $1 segment. Therefore the use of more strict criterion of $2 segments would markedly reduce sensitivity because of the frequent occurrence of ischemia limited to 1 segment. However, this theory fails to explain the significant reduction in sensitivity in myocardial regions remote from the infarct zone when criterion of ischemia in $2 segments was used. The frequent DECEMBER 1, 1998
FIGURE 2. The positive predictive value of ischemic pattern in each of the 16 segments for the diagnosis of significant stenosis of the related coronary artery. Code numbers of the segments are the same as shown in Figure 1.
occurrence of ischemia confined to 1 segment remote from the infarct region may be due to a different threshold for ischemia between the infarct-related and remote regions. Periinfarction ischemia may occur concomitantly with the possibility of reaching an end point (angina, electrocardiographic changes, or maximal dose) before ischemia becomes more extensive.4 Comparison with previous studies: Bach et al13 studied 39 patients with a false-positive DSE among 342 studies. They found that false-positive findings tended to involve small wall motion abnormalities that are frequently located in basal segments of the posterior myocardial circulation.13 When these investigators limited the diagnosis of CAD in the posterior circulation to wall motion abnormalities that involve at least 2 myocardial segments or those that involve more than only basal segments, the incidence of false-positive studies decreased by 25.5% and 30.8%, respectively. However, the sensitivity and specificity of DSE using criteria of abnormalities in $1 or $2 segments were not assessed. Latcham et al12 reported 7 false-positive DSE studies among 89 patients who underwent coronary angiography. They concluded that false-positive DSE often involves the inferobasal and midposterobasal left ventricular segments and that recognition of this pattern increased DSE specificity and could decrease test sensitivity. In our study, we did not find a difference in the specificity of DSE in the 3 vascular regions despite the use of $1 segment to define an abnormal test. Additionally, the positive predictive value of an ischemic pattern in each of the 16 myocardial segments for the diagnosis of significant stenosis of the related artery was not different. This approach is more relevant than reporting the number of false-positive responses in each segment because this number may be influenced by the prevalence of the disease in the related artery and the frequency of the occurrence of an ischemic response in a particular segment, which may yield different results in different patient populations.
Study limitations: Most of the study patients (76%) had significant CAD. This may tend to accentuate the reduction in sensitivity and dampen the improvement in specificity when ischemia is considered in $2, rather than $1, myocardial segment. However, even in patients without previous myocardial infarction, the criterion of ischemia in $2 segments failed to improve the accuracy despite the fact that the prevalence of CAD was only 60% in these patients. These results represent the experience of our center and will depend in part on how conservative the reviewers are in scoring ischemia and their recognition of the normal pattern of myocardial thickening and wall motion in different myocardial regions, particularly the basal segments of the posterior circulation which have been implicated in false-positive studies by some investigators.12,13 Therefore, further studies are needed to confirm our results.
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