Int J Cardiovasc Imaging (2008) 24:495–502 DOI 10.1007/s10554-007-9289-6
ORIGINAL PAPER
Dipyridamole stress echocardiography stratifies outcomes of asymptomatic patients with recent myocardial revascularization Andrea Rossi Æ Tiziano Moccetti Æ Francesco Faletra Æ Paolo Cattaneo Æ Mariagrazia Rossi Æ Elena Pasotti Æ Cecilia Fantoni Æ Claudio Anza` Æ Massimo Baravelli
Received: 5 September 2007 / Accepted: 10 December 2007 / Published online: 22 December 2007 Ó Springer Science+Business Media B.V. 2007
Abstract Background Patients with previous myocardial revascularization, even if symptom-free, remain at risk of subsequent cardiac events, so that a non-invasive tool able to stratify this population is wishful. Objectives To assess the prognostic value of dipyridamole stress echocardiography (DipSE) in a population of asymptomatic patients following complete myocardial revascularization, either by coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). Methods We retrospectively evaluated 104 consecutive symptomfree patients (mean age 67 ± 9.3 years, 75 males) with recent (\12 months) complete myocardial revascularization (48% PCI, 52% CABG) undergoing DipSE. Ischemia was defined as the onset of a new or worsening wall motion abnormality during DipSE. The composite end point of the study was cardiac death and non-fatal acute coronary syndrome. Results
Myocardial ischemia was identified in 23 patients (22.1%). During a mean follow up of 21 months, 7 (30.4%) out of these patients suffered cardiac events. Among the remaining 81 patients (77.9%) with negative DipSE results, 7 (8.6%) experienced cardiac events. At multivariable analysis only a positive DipSE (odds ratio 3.9, P = 0.03), wall motion score index at peak of stress (OR 3.6, P = 0.04) and a prior myocardial infarction (odds ratio 3.5, P = 0.04) achieved statistical significance for cardiac events. Moreover, DipSE effectively stratified patients into a high and low risk group according to presence of inducible ischemia (event rate per year 16% vs 4.8%, P = 0.02). Conclusions DipSE yields appropriate risk stratification and provides incremental prognostic value over clinical variables even in asymptomatic patients with prior complete myocardial revascularization. A negative DipSE portends a benign prognosis (\5% event rate/year) in such population.
A. Rossi T. Moccetti F. Faletra M. Rossi E. Pasotti Department of Cardiology, Cardiocentro Ticino, Lugano, Switzerland
Keywords Angioplasty Coronary artery bypass Dipyridamole Echocardiography Stress Myocardial revascularization
A. Rossi P. Cattaneo C. Anza` M. Baravelli (&) Department of Cardiology and Cardiovascular Intensive Rehabilitation, Multimedica Holding S. Maria, Castellanza, Varese, Italy e-mail:
[email protected] C. Fantoni Division of Cardiovascular Interventional Radiology, IRCCS Policlinico San Donato, San Donato Milanese, Italy
Abbreviations CABG Coronary artery bypass grafting DipSE Dipyridamole stress echocardiography PCI Percutaneous coronary intervention STEMI ST-segment elevation myocardial infarction
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UA/ NSTEMI WMSI
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Unstable angina/non ST-segment elevation myocardial infarction Wall motion score index
in symptom-free patients with recent complete surgical or percutaneous coronary revascularization.
Methods Introduction Recent American College of Cardiology/American Heart Association guidelines [1] do not recommend a routine stress test for myocardial ischemia in asymptomatic patients after coronary revascularization, either surgical or percutaneous, suggesting a symptom-driven provocative testing strategy. However, development of clinically silent bypass graft occlusion and coronary artery restenosis occur frequently after myocardial revascularization and remain a major clinical problem; therefore, a noninvasive tool able to predict the risk of subsequent cardiac events is wishful in such patients. Given the intrinsic limitations and low prognostic accuracy of exercise ECG stress testing [2–4], together with the need to document the site of ischemia, stress imaging techniques should be preferred in this group [5]. In particular, some studies have recently demonstrated the prognostic utility of myocardial perfusion imaging in asymptomatic patients following coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) [6–8]. In this scenario, however, pharmacological stress echocardiography could be the test of choice considering its availability, feasibility and lower cost compared to nuclear techniques [9, 10]. In fact, over the last 20 years, pharmacological stress echocardiography, with both dipyridamole and dobutamine, has been established as an accurate tool for a noninvasive prognostic assessment in patients with suspected or known coronary artery disease [11, 12] or in patients at high cardiovascular risk, such as subjects with diabetes mellitus [13, 14] or hypertension [15, 16]. However, data regarding the prognostic value of pharmacological stress echocardiography in patients with previous myocardial revascularization are few [17] and the usefulness of this technique remains unclear in such population, mainly in patients without symptoms of ischemia. Aim of our study was therefore to verify the prognostic value of dipyridamole stress echocardiography (DipSE)
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This is a retrospective observational single center study. We reviewed all 321 DipSE performed in our Cardiology Department between 1997 and 2000 and we selected 104 consecutive asymptomatic patients (75 male, mean age 67 ± 9.3 years) who underwent recent (\12 months) complete myocardial revascularization either surgical or percutaneous. An anatomically complete revascularization was considered accomplished when all major epicardial vessels with clinically significant stenoses were treated, irrespective of the underlying myocardial function. Significant stenosis was defined as[70% narrowing of the arterial lumen by coronary angiogram. Exclusion criteria included moderate-to-severe left ventricular dysfunction (left ventricular ejection fraction \40%) and prior ventricular tachycardia or fibrillation. The study protocol conforms to the ethical guidelines of the Declaration of Helsinki. Patients gave inform consent to data revision and analysis.
Dipyridamole stress protocol A complete basal Doppler and two-dimensional examination was performed in all patients with a Sonos 4500 ultrasound system (Hewlett Packard). No anti-ischemic medication was discontinued before echo-stress testing. As previously described [18], the dipyridamole infusion protocol consisted of an initial dose of 0.56 mg/kg over 4 min, increasing by 0.28 mg/kg over 2 min, without coadministration of atropine. Patients were monitored continuously by a 12-lead electrocardiogram and blood pressure was recorded every minute. Criteria for test interruption were onset of new wall motion abnormalities, severe angina pectoris, horizontal or downsloping ST-segment depression [2 mm, prolonged hypotension or blood pressure [220/120 mmHg, supraventricular or ventricular significant arrhythmias. Intravenous aminophylline was available to reverse potential side effects of dipyridamole.
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Echocardiographic analysis Standard echocardiographic views were obtained at baseline, during dipyridamole infusion and during recovery; the images were digitized in a quad screen format and evaluated by an experienced operator. Left ventricular mass was determined by using the Deveroux formula according to the recommendations of the American Society of Echocardiography [19]. Left ventricular mass was divided with body surface area to obtain the left ventricular mass index. Left ventricular hypertrophy was defined as left ventricular mass index C 110 g/m2 in women or 131 g/m2 in men. Myocardial ischemia was judged to be present when any new regional wall motion abnormalities or worsening of preexisting ones was detected. Left ventricular wall motion was evaluated with a 16segments model [20] and every segment was scored with a 4-points scoring system, where 1 is normal wall motion, 2 hypokinetic, 3 akinetic and 4 dyskinetic; wall motion score index (WMSI) was calculated both at baseline and at the peak of dipyridamole infusion by dividing the sum of segments scored by the total number of interpreted segments.
Follow-up Information about major cardiac events and causes of hospitalizations were collected in all patients. Cause of death was classified using all available sources of information including hospital records or by interviewing relatives and referring physicians. Patients were followed until the occurrence of a cardiac event or the last available examination. The composite study end-point was defined as major spontaneous cardiac events: cardiac death and nonfatal acute coronary syndrome. Cardiac death has been defined as death occurring after an acute coronary syndrome, heart failure, or sudden cardiac death assumed to be due to ventricular arrhythmias. Sudden cardiac death was defined as death occurring instantaneously, within 60 min of a change in symptoms or unexpectedly during sleep. Acute coronary syndrome encompassed the spectrum of symptomatic manifestations of myocardial ischemia including ST-segment elevation myocardial infarction (STEMI) [21] and unstable angina/non ST-segment elevation myocardial infarction (UA/NSTEMI) [22]. The diagnosis of
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STEMI was made according to the presence of persistent ST segment elevation and an increase of cardiac isoenzymes (creatine kinase MB or troponine) in an appropriate clinical setting (chest discomfort or anginal equivalent); UA/NSTEMI was defined by electrocardiographic ST-segment depression or T-wave inversion with negative (UA) or positive (NSTEMI) cardiac biomarkers of necrosis.
Statistical analysis Data are expressed as mean ± SD. Comparison between groups have been performed using Student’s test and chi-square test or Fisher’s exact test where appropriate. Initial univariable descriptive analyses have been performed for the following variables: age (\65 or [65 years), male gender, family history of coronary artery disease, hypercholesterolemia, hypertension, cigarette smoking, diabetes, prior myocardial infarction, left ventricular hypertrophy, presence of ischemia during DipSE, WMSI at baseline and at peak of echo-stress. Variables predictive of survival by univariable analysis (with P \ 0.1) have been then entered in a Cox proportional hazards regression model to determine their significance as independent predictors of survival in multivariable analysis. The differences in risk were expressed as odds ratio (OR) with the corresponding 95% confidence interval (CI). Event-free curves have been generated using the Kaplan-Meier method and groups have been compared by log-rank test. A value for P \ 0.05 has been considered statistically significant.
Results Baseline clinical, echocardiographic and angiographic findings of the study population are summarized in Table 1. Notably, patients with ischemia at DipSE were more frequently diabetics and had more frequently a history of hypertension or multivessel disease compared with patients with no ischemia. Moreover, among patients with previous CABG, prevalence of subjects with ischemia was significantly higher compared to patients with previous PCI. DipSE were performed 7.3 ± 2.8 months (median 8, range 2–11) after coronary revascularization. Myocardial
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Table 1 Baseline clinical, echocardiographic and angiographic findings of the study population according to results of dipyridamole stress echocardiography (ischemia, no-ischemia)
Male
All patients (104)
Ischemia (23)
No-ischemia (81)
P value
75 (72)
17 (72)
58 (74)
0.54
Age (years)
67 ± 9
68 ± 7
66 ± 10
0.11
Diabetes
27 (26)
10 (43)
17 (21)
0.04
Family history of CAD
47 (45)
10 (43)
37 (45)
0.33
Hypertension
46 (44)
16 (70)
30 (37)
\0.01
Smoking
50 (48)
11 (48)
41 (51)
0.20
Obesity
26 (25)
6 (26)
20 (25)
0.85
Hypercholesterolemia
74 (71)
16 (70)
59 (71)
0.70
Prior MI
52 (51)
12 (52)
40 (50)
0.40
LVEF (%)
53 ± 12
51 ± 14
54 ± 8
0.09
LV hypertrophy
39 (38)
24(62)
15(38)
0.01
WMSI at baseline
1.3 ± 0.2
1.4 ± 0.3
1.2 ± 0.2
0.06
WMSI at peak of stress
1.6 ± 0.6
1.8 ± 0.7
1.4 ± 0.6
\0.01
43 61
41 59
46 66
Medications (%) ACE-I/ARB Beta-Blockers
0.30 0.08
Calcium-antagonists
32
33
31
0.80
ASA
89
86
91
0.12
Statine
64
62
69
Monovessel disease
34 (32)
4 (18)
30 (37)
\0.01
Multivessel disease
70 (68)
19 (82)
51 (63)
0.01
PCI
50 (48)
7 (31)
43 (53)
0.02
CABG
54 (52)
16 (69)
38 (47)
0.02
0.09
Percentages are indicated in parenthesis. ACE-I, Angiotensin converting enzyme-inhibitors; ARB, AT1-receptor blockers; ASA, acetylsalicylic acid; CABG, coronary artery bypass grafting; CAD, coronary artery disease; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; WMSI, wall motion score index
ischemia was identified in 23 patients (22.1% of total). During a mean follow up of 21.2 ± 10.7 months (range 4–34 months), 7 (30.4%) of these patients suffered cardiac events (1 cardiac death, 2 STEMI, 4 UA/ NSTEMI). Among the remaining 81 patients (77.9% of total) with negative DipSE results, 7 (8.6%) experienced cardiac events (1 STEMI, 6 UA/NSTEMI). At univariable analysis, positive DipSE (OR 6.3, P = 0.007), WMSI at peak of dipyridamole infusion (OR 4.2, P = 0.02) , prior myocardial infarction (OR 4.1, P = 0.03), male gender (OR 3.5, P = 0.04) and hypercholesterolemia (OR 3.4, P = 0.05) showed a significant prognostic value in predicting major cardiac events. At multivariable analysis only a positive DipSE (OR 3.9, P = 0.03), WMSI at peak of stress (OR 3.6,
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P = 0.04) and a prior myocardial infarction achieved statistical significance in predicting major cardiac events (OR 3.5, P = 0.04) (Table 2). The 2-year event-free survival rate (Fig. 1) was 91% in patients with negative DipSE and 69% among those with positive DipSE (logRank P = 0.04). Event rate per year was 16% among patients with inducible ischemia compared to 4.8% (P = 0.02) in patients with negative DipSE.
Discussion The findings of present study demonstrate that DipSE yields appropriate risk stratification and provides incremental prognostic value over clinical variables
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Table 2 Univariable and multivariable predictors of cardiac events Univariable analysis OR
95% CI 1–12.2
Multivariable analysis P value
OR
95% CI
P value
0.04
2
0.7–11.3
0.12
1.4
0.9–13.2
0.49
3.5
1.9–14.7
0.04
Sex
3.5
Age
2.4
0.7–8.1
0.14
Family history of CAD
1.2
0.4–3.8
0.70
Hypercholesterolemia
3.4
Hypertension
1.2
0.4–3.7
0.64
Obesity
1.1
0.3–3.5
0.94
Smoking
1.1
0.3–3.4
0.88
Diabetes
2.1
0.6–7
0.13
Prior MI
4.1
1.1–15
0.03
LV hypertrophy
1.4
0.5–5.2
0.46
WMSI at baseline
2.5
0.9–8.7
0.10
WMSI at peak of stress
4.2
1.3–13.2
0.02
3.6
1.6–18.9
0.04
Positive DipSE
6.3
1.6–24.6
0.007
3.9
1.7–23.8
0.03
1–12.5
0.05
CAD, coronary artery disease; CI, confidence interval; DipSE, dipyridamole stress Echocardiography; LV, left ventricular; MI, myocardial infarction, OR, odds ratio; WMSI, wall motion score index
even in asymptomatic patients with recent complete myocardial revascularization, either surgical or percutaneous. A negative DipSE indicates a benign prognosis in such population (\5% event rate/year). Although the usefulness of any stress testing in asymptomatic patients following coronary revascularization has been questioned [1], the prognostic stratification for cardiac events remains a pivotal clinical problem in this population.
Exercise ECG stress testing is a proved method that has been used for the detection of ischemic heart disease and the assessment of its prognosis. Nevertheless, false positive results are commonly observed in presence of resting ECG abnormalities following CABG or PCI [2, 3]. Moreover, patients are quite deconditionated and debilitated after surgical myocardial revascularization, showing a reduced functional capacity which may also contribute
Fig. 1 Kaplan-Meier survival curves (considering major cardiac events as an end point) in patients stratified according to presence or absence of myocardial ischemia at dipyridamole stress echocardiography
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to lower prognostic accuracy of exercise ECG testing [3]. In addition to enhancing the diagnostic capacity of ECG stress testing, imaging techniques provide adjunctive information on the location and severity of ischemia which have important implications for the prognosis of such patients [5]. In particular, recent studies [6–8] suggested the prognostic utility of myocardial perfusion imaging stress testing in symptom-free patients with prior CABG or PCI. Lauer et al. [6] demonstrated that Thallium-201 myocardial perfusion study is a significant predictor of death and myocardial infarction in 873 asymptomatic patients after a procedure of surgical revascularization. During 3 years follow up, patients with thallium-perfusion defects were more likely to die (relative risk 2.78) or suffer a major event (relative risk 2.63). Sarda et al. [7] demonstrated the usefulness of Thallium-201 myocardial scintigraphy in predicting cardiac death or nonfatal myocardial infarction in a population of 115 asymptomatic patients after CABG; reversible defects were the only significant predictors of total events during a mean follow up of 35 months (relative risk 1.13, P = 0.05). Rajagopal et al. [8] analyzed the outcomes of 370 patients with (89) and without (281) symptoms of ischemia who underwent exercise nuclear scintigraphy after coronary stenting. At multivariable analysis, scintigraphic evidence of ischemia predicted death or myocardial infarction in the whole population during a median follow-up of 30 months (hazard ratio 2.08, P = 0.008). Presence of ischemia similarly predicted events in 281 patients who had no symptoms at the time of stress testing (hazard ratio 2.19, P = 0.015). However, nuclear techniques are not readily available in all hospitals and require trained operators and expensive technologies. In this framework, pharmacological stress echocardiography could be the test of choice considering its diagnostic accuracy, feasibility and lack of radiation risk [9, 10]. A recent review [23] including 13 studies with a total of 989 patients showed a high diagnostic value of stress echocardiography performed 3–6 months after primary PCI for detecting significant restenosis (mean sensitivity of 74% and mean specificity of 87%). In particular, three studies [24–26] of this review examined the diagnostic value of DipSE performed after successful PCI using accelerated
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high-dose protocol. The two studies reported by Pirelli et al. [24, 25] investigated a population of asymptomatic patients 3 months and 1 year after PCI. Sensitivity for the detection of restenosis were 71% and 75%, specificity was 90% and 92%, respectively. Scherhag et al. [26] confirmed the high diagnostic accurancy of DipSE in post-PCI patients with and without angina and demonstrated that its diagnostic value can be improved by atropine coadministration. Nevertheless, Bountioukos et al. [17] have been the only ones to assess the prognostic power for cardiac events of pharmacological stress echocardiography after myocardial revascularization. The authors demonstrated that dobutamine stress echocardiography is an independent predictor of the composite end-point cardiac death, myocardial infarction and late myocardial revascularization in 332 consecutive patients following CABG or PCI (hazard ratio 2.1). Among patients with ischemia event free survival did not differ significantly between patients with and patients without a history of angina pectoris. However, exact prevalence of angina in whole population at the time of stress testing was not clearly stated. Differently, the present study demonstrates the prognostic value of DipSE in a population specifically including only asymptomatic patients after complete surgical or percutaneous coronary revascularization with left ventricular ejection fraction of at least 40%. We enrolled patients with complete myocardial revascularization in order to determine the prognostic significance of de novo ischemic regions detected by DipSE. From this perspective, presence of nonrevascularized territories could contribute to false positive results and to decreased specificity of test, limiting in turn its prognostic interpretation [27]. Furthermore, recent studies [28, 29] suggest that ischaemia at echo-stress is not the main determinant of prognosis in patients with ischaemic left ventricular dysfunction whereas myocardium viability is a major contributor and a strong predictor of cardiac events. Given these findings, we focused on ischemia as prognostic stratifier only in patients with preserved or mild impaired left ventricular function. Additionally, our study was performed using dipyridamole instead of dobutamine as pharmacological stressor. Although these agents provide similar
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prognostic value and diagnostic accuracy in patients with coronary artery disease [30, 31] , dipyridamole seems to show higher safety and feasibility during stress procedure [32]. While coadministration of atropine increases diagnostic accuracy of accelerated high-dose DipSE [26], recent data [11] showed that a positivity of test after atropine coadministration yielded no incremental risk of future cardiac events compared to test negativity; in others words, we chose the more conservative protocol in the setting of prognostic stratification. Finally, differently from study of Bountioukos et al. [17] including late revascularization as softer end-point, our data indicate that DipSE confirms as a significant predictor of major spontaneous cardiac events in this subset of patients. Our observational follow-up indicates a better mid-term prognosis and a lower rate of events in patients with negative DipSE as compared to patients with ischemia (4.8% and 16% per year, respectively). These conclusions have important implications because they suggest that DipSE test can be used to stratify patients after a procedure of myocardial revascularization into a high risk group that needs aggressive therapy to prevent cardiac events, and a low risk group that can be followed and managed conservatively. In conclusion, although practice guidelines have argued against routine screening of asymptomatic patients after coronary revascularization, our as well as other series suggest that stress imaging test, in particular DipSE, yields appropriate risk stratification and provides incremental prognostic value over clinical variables in this population. Our data help to confirm that this technique represents a first-line, low-cost, and generally available screening tool that may stratify the risk of asymptomatic and stable patients after myocardial revascularization.
Study limitations This is an observational retrospective study, including a limited number of patients. Therefore, it’s hard to jump to prognostic conclusions and further prospective studies with larger populations of asymptomatic patients are needed to confirm the prognostic value of DipSE. Additionally, a relatively short follow-up
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period and a small number of events may prevent generalization of our results. Whether routine DipSE in asymptomatic patients following myocardial revascularization should be recommended is a pivotal question with important implications. In fact, the indiscriminate use of diagnostic tools would be an economically costly undertaking for medical care. We need therefore further larger studies with cost-effectiveness analysis of these techniques.
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