Prognostic interaction between viability and residual myocardial ischemia by dobutamine stress echocardiography in patients with acute myocardial infarction and mildly impaired left ventricular function

Prognostic Interaction Between Viability and Residual Myocardial Ischemia by Dobutamine Stress Echocardiography in Patients With Acute Myocardial Infarction and Mildly Impaired Left Ventricular Function Riccardo Bigi, MD, Alessandro Desideri, MD, Jeroen J. Bax, MD, PhD, Alfonso Galati, MD, Claudio Coletta, MD, Cesare Fiorentini, MD, and Paolo M. Fioretti, MD, PhD Dobutamine stress echocardiography (DSE) accurately detects viable myocardium and residual ischemia in patients with acute myocardial infarction (AMI). The prognostic interaction of viability and ischemia has not been completely clarified in these patients. This study assesses the long-term effect of viability, ischemia, or their combination on survival in patients with AMI and mildly impaired left ventricular (LV) function. Four hundred eleven patients (age 57 ⴞ 9 years) underwent predischarge DSE (up to 40 ␮g/kg/min plus atropine if needed) after uncomplicated AMI and were prospectively followed for 23 months (range 1 to 78). According to DSE findings, patients were divided into 4 groups: viability only, ischemia only, combination of viability and ischemia, and scar. Adverse outcome occurred in 64 patients: 34 patients had hard events (9 cardiac deaths,

25 nonfatal AMI) and 30 patients had unstable angina requiring hospitalization. The combination of viability and ischemia, diabetes mellitus, and non–Q-wave AMI were significant predictors of all events at univariate and multivariate analysis. The same variables were also univariate predictors of hard events, but multivariate analysis indicated only the combination of viability and ischemia and diabetes as independent predictors. The eventfree survival of patients with combined viability and ischemia was significantly lower (hazard ratio 3 [95% confidence interval 1.8 to 11]) compared with patients with ischemia only. Thus, viability and ischemia show a significant adverse prognostic interaction in patients with AMI and preserved LV function. 䊚2001 by Excerpta Medica, Inc. (Am J Cardiol 2001;87:283–288)

he assessment of inotropic reserve during low-dose and wall motion deterioration during high-dose T dobutamine stress echocardiography (DSE) allows si-

value of viability and ischemia or its combination on outcome has not been extensively investigated. Accordingly, the present study prospectively assesses the long-term effect of viability, ischemia, or their combination on survival in a large group of patients with AMI who underwent predischarge DSE.

multaneous identification of tissue viability1 and inducible ischemia.2 Several studies have addressed the prognostic value of DSE in the setting of acute myocardial infarction (AMI) with conflicting results.3– 8 In particular, some investigators have reported a beneficial effect of viability on prognosis,3,6 whereas a negative4,9 or neutral7,8 effect has been reported by others. Although differences in echocardiographic criteria of viability, left ventricular (LV) function, follow-up duration, and clinical end points in these different studies may play a role, the reason for this discrepancy has not been completely clarified. Furthermore, the relative From the Cardiovascular Research Foundation, “S. Giacomo” Hospital, Castelfranco, Venice, Italy; Department of Cardiology, University Medical Center, Leiden, The Netherlands; Division of Cardiology, “S. Spirito” Hospital, Rome, Italy; Division of Cardiology, “S. Paolo” Hospital and University of Milan, Milan, Italy; and IRCAB Foundation and Cardiology Institute, “S. Maria della Misericordia” Hospital, Udine, Italy. Manuscript received June 27, 2000; revised manuscript received and accepted August 2, 2000. Address for reprints: Riccardo Bigi, MD, via Visoli, 1, 23037 Tirano (SO), Italy. E-mail: [email protected]. ©2001 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 87 February 1, 2001

METHODS

Study population: The initial study population consisted of 545 consecutive patients admitted to a coronary care unit because of first AMI documented by typical chest pain lasting ⬎30 minutes, elevated creatine kinase and MB fraction, and electrocardiographic changes. Exclusion criteria were: (1) complicated infarction (overt heart failure, complex arrhythmia, and early recurrence of myocardial ischemia, n ⫽ 54), (2) prior infarction (n ⫽ 18), (3) ejection fraction ⬍40% (n ⫽ 52), and (4) technically inadequate acoustic window (n ⫽ 10). Thus, 411 patients were included in the present study and underwent predischarge DSE between February 1993 and October 1995, after withdrawal of ␤-adrenergic blocking agents for ⱖ5 halflives. Median follow-up was 330 days (first quartile 220 and third quartile 955). Age, sex, non–Q-wave infarction, thrombolysis, diabetes mellitus, smoking, 0002-9149/01/$–see front matter PII S0002-9149(00)01359-X

283

and hypertension were taken into account as clinical variables. Patients were referred for coronary angiography and eventual revascularization by their attending physician, who were unaware of study goals. The study was approved by the institutional review commitee and the subjects gave informed consent. Dobutamine stress echocardiography: DSE was performed 5 to 11 days after AMI according to a protocol based on 3-minute stages of 5, 10, 20, 30, and 40 ␮g/kg/min infusion, plus additional atropine up to 1 mg, if required, to achieve the 85% of age-predicted maximum heart rate. Metoprolol was used as antagonist. Twelve-lead electrocardiogram and 2-dimensional echocardiogram were continuously monitored during the test and up to 10 minutes after the end of the infusion. A 12-lead electrocardiogram was recorded each minute and cuff blood pressure was taken at the end of each infusion stage. Standard echocardiographic images were digitally stored in a side-byside cine loop format for off-line analysis by 2 experienced observers; in case of disagreement, a third observer reviewed the images and a consensus was achieved. The LV wall was divided into 16 segments that were scored as 1 ⫽ normal, 2 ⫽ hypokinetic, 3 ⫽ akinetic, or 4 ⫽ dyskinetic, and assigned to a predefined coronary artery territory.10 A wall motion score index (WMSI), representing the ratio between the sum of scores and the number of visualized segments, was calculated at baseline and at the low and high doses of dobutamine. Tests were discontinued in case of new wall motion abnormalities in ⬎2 segments. Wall motion changes were defined as homozonal if they occurred in the same vascular territory, and heterozonal if they occurred in a different vascular territory from the culprit vessel. Akinesia that developed into dyskinesia was not taken into account.11 Nonechocardiographic criteria for discontinuing the test were: diagnostic ST-segment changes, severe chest pain, significant arrhythmias, systolic blood pressure ⬎230 mm Hg or a decrease of ⬎30 mm Hg, and intolerable symptoms. The patients were divided into 4 groups according to DSE result: (1) biphasic response (combination of viability and ischemia): low-dose WMSI improvement followed by a high-dose deterioration; (2) worsening (ischemia only): direct WMSI deterioration at low or high dose; (3) sustained improvement (viability only): low-dose WMSI improvement that was maintained at high-dose; (4) no change (scar): no change in WMSI during the entire protocol. A rest-to-peak WMSI increase indicated the extension of dobutamine-induced asynergies. Wall motion analysis was performed on a “per-patient” basis for the entire ventricle. Follow-up: Outcome was determined from patient interviews, hospital chart reviews, and/or telephone interviews with a close relative or the referring physician. Events were defined as cardiac death, nonfatal infarction, and unstable angina requiring hospitalization. Death was defined as cardiac if strictly related to proved cardiac causes (fatal reinfarction, acute heart failure, or malignant arrhythmias). Infarction was di284 THE AMERICAN JOURNAL OF CARDIOLOGY姞

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TABLE 1 Clinical and Echocardiographic Data of the Study Population (n ⫽ 411) Clinical data Age (yrs) Women Anterior infarction Inferior infarction Non–Q-wave infarction CPK (IU/ml) Hypertension Diabetes Smoking Thrombolysis Stress echocardiography data Rest WMSI Low-dose WMSI Peak WMSI Dobutamine dose (␮g/kg/min) Atropine administration Maximal heart rate Rate-pressure product

57 55 140 215 56 1,993 98 52 238 221

⫾9 (13%) (34%) (52%) (14%) ⫾ 1,172 (24%) (13%) (58%) (54%)

1.48 1.39 1.62 36.6 192 127 20,360

⫾ 0.28 ⫾ 0.24 ⫾ 0.30 ⫾ 6.6 (47%) ⫾ 17 ⫾ 3,430

CPK ⫽ creatine phosphokinase.

agnosed on the basis of documented electrocardiographic changes and typical cardiac enzyme release. Unstable angina was defined as “crescendo angina” at rest or minimal effort angina in the absence of electrocardiographic and enzymatic changes indicating myocardial infarction. Cardiac death and nonfatal infarction were defined as hard events. Only the worst event was taken into account for statistical analysis to avoid overlap. All patients undergoing revascularization were censored at the time of procedure, because it was considered to cause underestimation of the spontaneous event rate. Statistical analysis: Continuous variables are expressed as mean ⫾ 1 SD and were compared by the unpaired 2-sample t test. The 95% confidence interval (CI) and quartiles are reported when appropriate. Proportions were compared by chi-square statistics. The individual effect of clinical and DSE variables on survival was evaluated by Cox’s proportional hazard model using a stepwise forward procedure.12 At each step a significance of 0.1 was required to enter into the model. All clinical variables and the following echocardiographic variables were selected for examination: resting and peak WMSI, rest-to-peak WMSI variation, maximal dobutamine dose, biphasic, worsening, sustained improvement, and no change pattern. The log-rank test was used to compare Kaplan-Meier event-free survival curves. A p value of ⬍0.05 was considered statistically significant. The SPSS statistical package (release 7.5.1 for Microsoft Windows) was used for analysis.

RESULTS Clinical and echocardiographic characteristics of the study population are listed in Table 1. Two major adverse reactions were observed: 1 ventricular fibrillation that occurred 10 minutes after halting dobutamine infusion, which was effectively reverted by electrical defibrillation, and 1 sustained ventricular FEBRUARY 1, 2001

58 ⫾ 9

59 ⫾ 8

56 ⫾ 9

57 ⫾ 9

Age (yrs)

15

17

11

6

Women (%)

12

10

14

20

Non–Q-wave MI (%)

57

57

51

48

T-lysis (%)

13

17

13

9

Diabetes (%)

56

52

69

61

Smoking (%)

23

32

15*

28

Hypertension (%)

1.42 ⫾ 0.28

1.62 ⫾ 0.31

1.33 ⫾ 0.24†

1.55 ⫾ 0.27

Resting WMSI

1.42 ⫾ 0.28

1.46 ⫾ 0.26

1.36 ⫾ 0.27

1.38 ⫾ 0.25

Low-dose WMSI

1.42 ⫾ 0.28

1.4 ⫾ 0.30

1.65 ⫾ 0.28

1.79 ⫾ 0.30†

Peak WMSI

653 ⫾ 597

535 ⫾ 418

662 ⫾ 624

386 ⫾ 432‡

FU (d)

TABLE 2 Characteristics of Patients According to the Response Pattern to DSE

DSE Pattern

Biphasic (n ⫽ 50) Worsening (n ⫽ 148) Improvement (n ⫽ 41) No change (n ⫽ 172)

tachycardia at peak infusion. Premature termination of the test because of intolerable side effects was necessary in 2 patients. Dobutamine stress echocardiography: New wall motion abnormalities were found in 198 patients (homozonal in 142 and heterozonal in 56). The 4 response patterns were biphasic response in 50 patients (12%), direct worsening in 148 (36%), sustained improvement in 41 (10%), and no change in 172 patients (42%). Mean dobutamine dose in patients with positive DSE was 35.7 ␮g/kg/min (95% CI 34.7 to 36.7 ␮g/kg/min); its frequency distribution is shown in Figure 1. Clinical and DSE data of the individual groups are listed in Table 2. Outcome prediction: No patient was lost to followup. Sixty-four events (15.5%) were observed: 9 cardiac deaths, 25 nonfatal reinfarctions, and 30 episodes of unstable angina. Two patients died because of noncardiac reasons (1 cancer and 1 car accident). Six patients experienced ⬎1 event: nonfatal reinfarction following an episode of unstable angina in 5 patients and cardiac death following reinfarction in 1. The event distribution according to DSE result is listed in Table 3. Reinfarction occurred in the same coronary artery territory in 13 patients (9 with biphasic, 2 with worsening, 1 with sustained improvement, and 1 with no change pattern) and in a different vascular territory in 12 patients (1 with biphasic, 1 with worsening, 6 with sustained improvement, and 4 with no change in pattern). One hundred fourteen patients (28%) underwent myocardial revascularization (81 underwent bypass surgery and 33 underwent coronary angioplasty). Median time from the index DSE to revascularization was 180 days (first quartile 115, third quartile 335). No subject underwent direct coronary angioplasty. Revascularized patients received lower doses of dobutamine (34.2 ⫾ 7.5 vs 37.4 ⫾ 6.1, p ⬍0.0001) and had higher peak WMSI (1.69 ⫾ 0.31 vs 1.52 ⫾ 0.25, p ⬍0.0001) and more heterozonal ischemia (30 of 114 vs 26 of 297, p ⬍0.0001) compared with medically treated patients. No significant difference was found between the 2 groups regarding for clinical variables.

*p ⬍0.05 versus improvement in hypertension (32%); †p ⬍0.01 versus all; ‡p ⬍0.05 versus all. FU ⫽ follow up; T-lysis ⫽ thrombolysis.

FIGURE 1. Frequency distribution of maximal dobutamine dose in patients with positive test result.

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TABLE 3 Cardiac Events According to DSE Results

Unstable angina (n ⫽ 30) Reinfarction (n ⫽ 25) Cardiac death (n ⫽ 9) Total (n ⫽ 64)

Biphasic (n ⫽ 50)

Worsening (n ⫽ 148)

Improvement (n ⫽ 41)

11 (22%) 10 (20%) 4 (8%) 25 (50%)

6 (4%) 3 (2%) 2 (1.4%) 11 (7.4%)

9 (22%) 7 (17.1%) 0 (0%) 16 (39.1%)

Revascularization was significantly more frequent in patients with biphasic response (22 of 50 [44%]) and direct worsening (56 of 148 [38%]) compared with those with sustained improvement (8 of 41 [19%], p ⬍0.05) or no change in pattern (28 of 172 [16%], p ⬍0.0001). Non–Q-wave infarction, diabetes mellitus, and biphasic pattern were univariate and multivariate (odds ratio [OR] 2.1, 95% CI 1.2 to 3.8; OR 2.8, 95% CI 1.5 to 5.1; and OR 2.6, 95% CI 1.4 to 5, respectively) predictors of all spontaneous events as well as univariate predictors of hard events. However, biphasic pattern and diabetes were the only multivariate predictors of hard events (OR 3.0, 95% CI 1.2 to 6.9 and OR 2.4, 95% CI 0.9 to 5.9, respectively). The biphasic pattern was associated with a significantly lower event-free survival (Figure 2) compared with worsening pattern in patients with ischemia (3, 95% CI 1.8 to 11 for all spontaneous events, and 4.4, 95% CI 2.2 to 34 for hard events). Conversely, no significant difference was found between sustained improvement and no change in patterns among patients with nonischemia.

DISCUSSION Because the beneficial effect of functional recovery on survival is expected to be critically correlated with the extent of LV dysfunction, the clinical relevance of myocardial viability has been mostly evaluated in patients with impaired LV function.2,3,6 However, this study demonstrates an unfavorable prognostic impact of the combination of myocardial ischemia and viability in patients with AMI and mildly impaired LV function. Of note, myocardial ischemia was prognostically significant only if associated with tissue viability. Although the recourse to revascularization in patients with extensive stress-induced ischemia may partially account for this finding, several points deserve further consideration. The sensitivity of stress echocardiography for detecting myocardial ischemia in dyssynergic segments was lower compared with nuclear techniques in previous studies that only used peak stress images.13–15 However, the biphasic response to DSE has been shown to be significantly more sensitive compared with direct wall motion worsening.16 Alternatively, it may reflect more severe myocardial ischemia, as suggested by its correlation with residual stenosis of the 286 THE AMERICAN JOURNAL OF CARDIOLOGY姞

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infarct-related artery17–19 and its superior ability to predict improved No Change contractile function after revascular(n ⫽ 172) ization.20,21 In the absence of myocardial ischemia, tissue contractility 4 (2.3%) in viable segments increases, which 5 leads to the appearance or improve(2.9%) ment of myocardial thickening. 3 However, if the coronary flow in(1.7%) 12 crease is limited by residual stenosis, (6.9%) this improvement is followed by a worsening that reflects the imbalance between myocardial oxygen demand and supply. Several studies, including a head-to-head comparison between DSE and myocardial perfusion scintigraphy, reported a relation between biphasic response and myocardial scintigraphic ischemia.16,17,22 In contrast, a biphasic response to incremental dosages of dobutamine has also been demonstrated in ischemic or short-term hibernating myocardium where the transient improvement was obtained at the expense of metabolic deterioration with subsequent lactate accumulation, myocardial acidosis, and wall thickening deterioration.17 It is possible that repetitive stunning in the infarct area may lead to morphologic changes, long-term mechanical dysfunction, or further cardiac events despite nearly normal absolute myocardial blood flow at rest. Our results provide the prognostic link to these observations by showing that the presence of viable but jeopardized myocardium is associated with increased incidence of cardiac events in nonrevascularized patients. Of note, although no death occurred among patients with sustained improvement on DSE, nonfatal events were more frequent than in patients with worsening and no change in patterns (Table 3), thus emphasizing the prognostic role of tissue viability. Survival analysis further reinforced these findings (Figure 2) and showed that events occurred significantly (p ⬍0.05) earlier in patients with biphasic response (1year event-free survival 71% compared with 93% of those with ischemia only, 90% of those with viability only and 88% of those with scar only). This confirms the clinical instability associated with the combination of viability and ischemia and is consistent with the hypothesis that cardiac events occurring in other groups are reflections of the progression of coronary artery disease, the clinical consequences of which are much less predictable by stress testing. This study also emphasizes the added value of using a high-dose protocol in DSE; the distribution of a maximal dose in patients with a positive test (Figure 1) clearly shows that the largest proportion of these patients would have been misclassified if only a low dose had been used. Diabetes and non–Q-wave infarction were the only clinical predictors of unfavorable outcome in this study; in particular, diabetes was an independent predictor of hard events. This confirms that, despite significant improvements in patient care, diabetic patients still represent a population at higher risk of morbidity and mortality for coronary artery disFEBRUARY 1, 2001

FIGURE 2. Kaplan-Meier curves of all and hard event-free survival according to DSE result. The biphasic pattern was associated with significantly lower event-free survival in patients with ischemic response. No significant difference was found between viability and nochange in pattern in patients with nonischemic response.

ease.23,24 Increased rates of early and late cardiac events have been reported in non–Q-wave infarction and this has been presumably attributed to the presence of viable but jeopardized myocardium within the perfusion zone of the infarct-related artery.25,26 However, the concept of non–Q-wave infarction as an “unstable” clinicopathologic entity requiring a more aggressive therapeutic approach has been recently questioned.27,28 Accordingly, we found that non–Qwave infarction predicted all spontaneous but not hard events. Comparison with previous studies: Sicari et al4 found viability at DSE to predict soft (unstable angina) but not hard (reinfarction and death) events in patients with AMI and mildly impaired LV function. Follow-up was only 9 months in their study and the hard event rate was very low, which may have underestimated the prognostic value of DSE. No independent prognostic value of viability was reported by Previtali et al7 and Salustri et al.8 However, these investigators did not separately analyze the prognostic value of ischemia and viability, thus including the biphasic response in the general group with positive DSE. This may have inflated the prognostic value of test positivity. Indeed, all events occurred in the group of patients with viability and ischemia in Previtali et

al’s study.7 Furthermore, Salustri et al8 reported that viability was associated with worse outcome only in case of biphasic response. Finally, because most patients underwent DSE on ␤-blocking therapy in all previous studies, a possible interference with the assessment of myocardial viability and ischemia cannot be ruled out. Study limitations: (1) Consecutive coronary angiography was not included in our study protocol, and therefore, the relation between DSE and coronary anatomy could not be evaluated. (2) Revascularization was not randomized and may have been influenced by a selection bias with consequent dilution of the prognostic value of DSE. However, revascularized patients had higher peak WMSI, more heterozonal ischemia, and received lower doses of dobutamine, indicating more severe or extensive ischemia. This suggests that revascularized patients may have been at higher risk and that selection bias likely did not account for differences in survival. 1. Pie´rard LA, De Landersheere CM, Berthe C, Rigo P, Kulbertus HA. Identification of viable myocardium during dobutamine infusion in patients with myocardial infarction after thrombolytic therapy: comparison with positron emission tomography. J Am Coll Cardiol 1990;15:1021–1031. 2. Geleijnse ML, Fioretti PM, Roelandt JRTC. Methodology, feasibility, safety

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