Prognostic Value of Myocardial Ischemia and Viability in Patients With Chronic Left Ventricular Ischemic Dysfunction
Background—Previous studies showed that thallium scintigraphy and dobutamine echocardiography were accurate, noninvasive ways of predicting contractile recovery after revascularization in patients with left ventricular (LV) dysfunction. However, the prognostic impact of such methods remains uncertain.
Methods and Results—We prospectively studied 137 consecutive patients with coronary disease and LV dysfunction who underwent exercise-redistribution-reinjection thallium scintigraphy and dobutamine echocardiography to identify myocardial ischemia and viability. A total of 94 patients subsequently underwent revascularization, and 43 underwent medical treatment. The primary endpoint was cardiac mortality, and mean follow-up was 33±10 months. Twenty-four patients died of cardiac causes. By Cox’s regression analysis, long-term survival was related to the extent of coronary disease, the presence of diabetes, type of treatment, the presence of ischemic myocardium as determined by thallium scintigraphy, and the presence of viable myocardium as determined by both tests. Three-year survival was greater in patients with ischemic myocardium (as determined by thallium scintigraphy) or viable myocardium (as determined by both tests) who underwent revascularization than in the other groups (P=0.018 with thallium; P<0.001 with dobutamine). Subgroup analyses indicated that among patients with 1- or 2-vessel disease, only those with ischemic or viable myocardium improved survival after revascularization, whereas in patients with 3-vessel or left main diseases, revascularization always improved survival, albeit more in the presence of ischemic or viable myocardium.
Conclusions—Among the parameters commonly available in patients with LV ischemic dysfunction, the presence of ischemic myocardium (as determined by thallium scintigraphy) and that of viable myocardium (as determined by dobutamine echocardiography) are independent predictors of subsequent mortality. These observations may be useful in the preoperative selection of patients for revascularization.
Over the past 50 years, ischemic heart diseases have become a widespread cause of morbidity and the leading cause of mortality in the economically developed countries of the Western world. Although the relative importance of coronary deaths has declined gradually during the last decade, coronary heart disease still accounts for approximately 25% of all deaths in the United States and Europe. Mortality rates are even higher in patients with severely depressed left ventricular (LV) function.1 Several studies showed that surgical revascularization can improve the survival and symptoms of heart failure in some patients.2 3 The potential benefits of revascularization should be balanced, however, with the higher surgical mortality of patients with LV dysfunction.4
Presumably, the beneficial effects of revascularization result from restoring blood supply to dysfunctional but viable myocardial regions, with subsequent improvement in regional and global LV function. During the past decade, delineation of viable from nonviable myocardium has become the focus of considerable attention and has fostered the development of several new modalities aimed at predicting the return of LV function after revascularization. Among these modalities, exercise-redistribution-reinjection thallium scintigraphy5 6 7 8 and low-dose dobutamine echocardiography7 8 9 10 11 have recently emerged as safe, noninvasive, and accurate means of identifying viable myocardium. Although existing data suggest that both imaging modalities are useful for predicting the return of contractile function after revascularization, few data are currently available on their potential value for predicting long-term survival. Accordingly, the aims of the present study were (1) to evaluate the potential prognostic value of exercise-redistribution-reinjection thallium scintigraphy and dobutamine echocardiography in patients with LV ischemic dysfunction and (2) to determine whether assessing myocardial viability by either means adds independent prognostic information to that provided by baseline clinical, hemodynamic, and angiographic data and by the assessment of myocardial ischemia alone.
Between October of 1991 and November of 1994, we prospectively studied 141 consecutive patients with coronary disease and LV dysfunction who had been referred to our institution for diagnostic cardiac catheterization. Four patients who subsequently underwent heart transplantation were excluded from the study. Among the 137 remaining patients, 117 had sustained at least 1 previous myocardial infarction, the most recent occurring 33 days before inclusion into the study. Patients were eligible for inclusion (1) if they had severe regional dysfunction in the anatomic distribution of a significantly narrowed or occluded epicardial artery as determined by contrast left ventriculography and (2) if the coronary arteries supplying the area of dysfunction were suitable for coronary bypass grafting (CABG) or percutaneous coronary angioplasty (PTCA). All patients underwent exercise-redistribution-reinjection thallium scintigraphy and low-dose dobutamine echocardiography during their hospital stay for cardiac catheterization. Subsequently, 94 patients underwent revascularization (72 by CABG and 22 by PTCA), and 43 patients were treated medically. No patient received an automatic implantable cardiac defibrillator. The decision concerning the choice of treatment was left to the referring cardiologist and was not based on the results of the viability studies. The study protocol was approved by the Ethical Committee of the University of Louvain Medical School.
Selective coronary arteriography and contrast left ventriculography were performed from the femoral approach and before the scintigraphic and echocardiographic studies. Significant coronary disease was defined as >70% luminal diameter stenosis in any major coronary branch. A total of 105 patients had ≥1 major epicardial coronary segment(s) occluded; of these 105 patients, 64 also had occlusion of the left anterior descending coronary artery, 29 had occlusion of the proximal circumflex artery, and 66 had occlusion of the right coronary artery. The remaining 32 patients had severe proximal stenoses on at least 1 major epicardial segment.
Exercise-redistribution-reinjection thallium scintigraphy and dobutamine echocardiography were performed and analyzed as previously described.8,11 Delineation of inducible ischemia with the 2 methods was performed using previously validated criteria.11 12 13 Patients were considered to have inducible ischemia by thallium scintigraphy if their defect extent score decreased by >3 grades between exercise and redistribution.11 12 Similarly, patients were considered to have inducible ischemia by dobutamine echocardiography in the presence of a new or the worsening of a preexisting wall motion abnormality in at least 1 myocardial segment.13 Delineation of reversible dysfunction with the 2 methods was also performed using previously validated criteria.12,13 Patients were considered to have viable myocardium by thallium scintigraphy if >50% of the dysfunctional segments exhibited a thallium uptake >50% at reinjection.12 Similarly, patients were considered to have viable myocardium on the basis of dobutamine echocardiography if wall motion score improved by at least 1 full grade in 2 adjacent akinetic segments from the same vascular territory during low-dose dobutamine treatment.13
Patients were followed-up for 33±10 months (range, 13 to 48 months). Survival status was obtained by telephone contact with the patients, their relatives, or the referring physician and from review of visit or hospital records. The cause of death was categorized as cardiac or noncardiac. Cardiac death was defined as death attributable to congestive heart failure, myocardial infarction, cardiac arrest, or sudden death (death within the first hour after the onset of symptoms).
Data were analyzed with BMDP New System Professional Edition statistical software.14 Data are reported as mean±SD and follow-up times as median and range. Groups were compared with χ2 tests for discrete variables and with a 2-way ANOVA with a Scheffé criterion for continuous variables. Survival curves were computed with the Kaplan-Meier method and compared using the log-rank χ2 test. A Cox’s model was used to adjust for the effects of baseline characteristics on survival. For this purpose, a preliminary model was built from which the results of the tests were excluded.15 The ability of myocardial ischemia or viability (with and without their interaction with treatment) to improve the prediction of death by the preliminary model was tested by the maximum partial likelihood ratio χ2 statistic. The assumption of proportional hazards was checked by complementary log plots. Relative hazard ratios for each specific covariate of the final models were computed as the exponential of the regression coefficient.16 The total hazard ratio in a particular patient was calculated as the product of all relative hazard ratios. As the models only included binary covariates, the baseline death rate corresponded to the death rate of patients with all covariates=0. A total hazard ratio >1/1 indicates an increase in death rate compared with baseline. Conversely, a hazard ratio <1/1 indicates a decrease in death rate compared with baseline.
The baseline characteristics of the study population are shown in Table 1⇓. During follow-up, 24 patients died of cardiac causes: 5 immediately postoperatively (in the intensive care unit), 6 of congestive heart failure, 2 of acute myocardial infarction, and 11 of sudden death. Among the patients who died during follow-up, 13 had undergone revascularization, and 11 others had received medical treatment. Figure 1⇓ shows the Kaplan-Meier survival curves in these 2 groups, together with that expected in the age- and sex-adjusted Belgian population.
Relation Between Myocardial Ischemia and Myocardial Viability
The proportion of patients exhibiting myocardial ischemia or viability by either thallium scintigraphy or dobutamine echocardiography is illustrated in Figure 2⇓. The concordance between thallium scintigraphy and dobutamine echocardiography for identifying myocardial ischemia and viability is shown in Figure 3⇓. Overall, the degree of agreement between the 2 methods was only modest (57% for myocardial ischemia, 63% for myocardial viability).
Relation of Myocardial Ischemia and Treatment Strategy to Cardiac Mortality
To assess the potential prognostic value of ischemic myocardium on long-term survival, the study population was subdivided twice (once for thallium scintigraphy and once for dobutamine echocardiography) into 4 subgroups composed of patients with or without myocardial ischemia who did or did not undergo revascularization. The different subgroups were similar with respect to demographic variables, risk factors, extent of coronary disease, history of previous myocardial infarction, and indices of global LV function.
As shown in Figure 4⇓, 3⇑-year survival was higher in patients with ischemic myocardium determined by thallium scintigraphy who underwent revascularization (91±4%) than in the 3 other subgroups (range, 73% to 75%; pooled value, 74±5% [logrank P=0.015]). By contrast, 3-year survival was lower in patients with ischemic myocardium determined by dobutamine echocardiography who underwent medical treatment (66±9%) than in the 3 other subgroups (range, 84% to 90%; pooled value, 85±4% [logrank P=0.006]).
Relation of Myocardial Viability and Treatment Strategy to Cardiac Mortality
To evaluate the potential impact of myocardial viability and treatment strategy on long-term survival, an analysis similar to that used for ischemia was performed. The study population was again subdivided twice (once for thallium scintigraphy and once for dobutamine echocardiography) into 4 subgroups composed of patients with or without myocardial viability who did or did not undergo revascularization. These different subgroups were also similar with respect to most variables, except for LV end-diastolic volume, which was larger in patients treated medically who lacked evidence of myocardial viability by dobutamine echocardiography.
As illustrated in Figure 5⇓, 3⇑-year survival was higher in patients with viable myocardium who underwent revascularization (91±4% with thallium scintigraphy; 95±3% with dobutamine echocardiography) than in any other patient subgroups (range, 71% to 78%; pooled value, 74±5% for thallium scintigraphy [logrank P=0.018] and 71±5% for dobutamine echocardiography [logrank P=0.0009]).
Cox’s Proportional Hazards Survival Analysis
To assess the potential additive prognostic value of myocardial ischemia and viability, a preliminary Cox’s survival model was built, on which the results of the stress tests were not included. This model used treatment as a fixed covariate. Among the demographic, clinical, hemodynamic, and angiographic variables (and their interaction with treatment) included, 5 covariates were independently associated with the time to death (Table 2⇓). The ability of the stress tests to improve the prediction of death by this preliminary model was tested in 4 different models, 2 for thallium scintigraphy and 2 for dobutamine echocardiography, in which the 5 preliminary covariates were used as fixed covariates. As shown in Table 2⇓, the presence of ischemic myocardium (determined by thallium scintigraphy) and the presence of viable myocardium (by both methods) added significant prognostic information to that provided by the 5 initial covariates. After multivariate analysis, however, only the presence of myocardial ischemia determined by thallium scintigraphy and the presence of myocardial viability determined by dobutamine echocardiography were independently related to long-term prognosis. Table 3⇓ shows the variables retained in the final multivariate models together with all partial hazard ratios. With the 3 models, diabetes and extensive coronary disease (3-vessel disease, left main stenosis, or both) were associated with an increased risk of death. This risk was reduced in patients undergoing revascularization. Evidence of ischemic myocardium by thallium scintigraphy or viable myocardium by either method in a patient undergoing revascularization was also associated with a reduced risk of death.
Table 3⇑ and Figure 6⇓ illustrate the potential clinical impact on individual patients of a strategy in which the variables retained in the dobutamine echocardiography model are considered. For instance, nondiabetic patients with moderate coronary disease who undergo revascularization have a 2.4-fold increase in mortality in the absence of viable myocardium (hazard ratio [HR]=2.4), but a 2.6-fold decrease in mortality in the presence of viable myocardium (HR=0.38). Similarly, the baseline risk of death in diabetic patients with moderate coronary disease treated medically is 8.9-fold higher than that of nondiabetic patients. If these patients undergo revascularization in the absence of viable myocardium, their risk of death decreases only marginally (HR=7.2). It decreases much more, however, in the presence of viable myocardium (HR=1.2). In all instances, except with nondiabetic patients with moderate coronary disease and nonviable myocardium, revascularization improved survival. The gain was significantly greater, however, in the presence of viable myocardium. Similar results were obtained when using thallium scintigraphy for assessing myocardial ischemia or viability.
The long-term outcome of patients with LV ischemic dysfunction is poor, particularly when they are treated medically.1 2 3 A major goal in the management of these patients is, thus, to identify those at risk for future adverse cardiac events so that active treatment can be initiated and these events can be prevented. Risk stratification in patients with LV ischemic dysfunction typically includes a combination of clinical, hemodynamic, and angiographic parameters.17 Recent studies using myocardial metabolic imaging with positron emission tomography (PET) have indicated that assessing myocardial viability also provides useful prognostic information in these patients,17 18 19 20 21 with an effect additive to that of the usual clinical assessment.21 Whereas PET is expensive and not widely available, exercise-redistribution-reinjection thallium scintigraphy and dobutamine echocardiography are less expensive and potentially more widely available methods that can also distinguish viable from nonviable myocardium. Until now, studies addressing the contribution of these techniques to the detection and treatment of viable myocardium have mainly concentrated on their ability to predict the return of contractile function after revascularization.5 6 7 8 The purpose of the present study was to establish the potential prognostic implications of identifying viable and/or ischemic myocardium by either of these 2 methods in patients with LV ischemic dysfunction. The results can be summarized as follows:
Long-term survival in patients with LV ischemic dysfunction was related to the extent of the underlying coronary disease, the presence of diabetes, and treatment strategy.
After adjusting for these clinical variables, the 3-year survival of patients undergoing revascularization was significantly better in the presence of myocardial ischemia or viability. In contrast, in patients receiving medical treatment, long-term survival was not influenced by the presence or absence of myocardial ischemia or viability.
In patients with viable or ischemic myocardium, 3-year survival was significantly better in patients undergoing revascularization as opposed to medical treatment. In patients with nonviable myocardium, outcome was not significantly influenced by treatment strategy.
Prognostic Implications of Myocardial Ischemia and Viability in Patients With Chronic LV Ischemic Dysfunction
The salient findings of our study relate to the impact of viable myocardium on the long-term outcome of patients with LV ischemic dysfunction. The presence of viable myocardium was evaluated in our study by exercise-redistribution-reinjection thallium scintigraphy and by low-dose dobutamine echocardiography. We and others5 6 7 8 9 10 11 previously showed that both methods accurately predict the return of regional and global LV function after revascularization. The present study demonstrates that, in addition, these 2 methods also provide valuable prognostic information, with significant therapeutic implications. Specifically, we showed that the presence of viable myocardium by either method and the presence of ischemic myocardium by thallium scintigraphy help identify patients who can benefit from revascularization. Indeed, in our study, the 3-year survival of patients with viable or ischemic myocardium who underwent revascularization was 91% to 95% (depending on the parameter used), a value that is remarkably similar to that expected in the age- and sex-adjusted Belgian population (93%). In contrast, in similar patients treated medically, 3-year survival was only 71% to 75%, thus demonstrating the need to proceed to revascularization in such patients. It is probable that the prognostic benefits of revascularization in patients with viable myocardium extend well beyond the simple prevention of recurrent ischemia and involve a direct effect on global LV function. In a subgroup of 43 patients with viable myocardium included in this study, we had previously shown that revascularization improved global LV ejection fraction by an average of 13%, a change that is likely to impact survival.8 In contrast, in 30 patients with nonviable myocardium, revascularization did not result in any significant changes in global LV function and barely prevented LV dilatation.8 Likewise, in the present study, revascularization had no major influence on long-term outcome in the absence of viable myocardium. This was particularly true for nondiabetic patients with moderately severe coronary disease and nonviable myocardium; in these patients, surgical revascularization tended to increase the risk of death 2.4-fold (Table 3⇑).
Recent studies have started to address the prognostic significance of viable myocardium in patients who do and do not undergo revascularization. Eitzman et al18 used PET to study the role of viable myocardium in the occurrence of adverse cardiac events in 80 coronary patients, 40 of whom underwent revascularization. Patients with viable myocardium who were not revascularized had significantly more events and were more likely to die than those undergoing revascularization. Similarly, in 79 patients with severe LV dysfunction undergoing metabolic imaging with PET, Di Carli et al20 showed that unrevascularized patients with viable myocardium had a greater likelihood of sudden cardiac death than patients undergoing revascularization. Similar findings were recently reported by Lee et al.21 Thus, with respect to the outcome of patients with viable myocardium, our results agree with those from these earlier reports. They differ, however, with respect to the outcome of patients with nonviable myocardium. Whereas in the studies of Eitzman et al,18 Di Carli et al,20 and Lee et al,21 patients with nonviable myocardium had an excellent prognosis (3-year survival, 82% to 100%), these patients definitely had a poorer outcome in our study. Our results are nonetheless in agreement with those of Yoshida and Gould,22 who used 82Rb and PET to identify myocardial viability, and with the more recent reports of Pagley et al23 and Petretta et al,24 who used thallium scintigraphy as a means of identifying viable myocardium. They also concur with those of Williams et al,25 who studied 136 medically treated patients with LV ischemic dysfunction with low-dose dobutamine echocardiography. Interestingly, in this latter study, the authors divided their population of patients with nonviable myocardium into 2 groups according to the presence of inducible ischemia at higher doses of dobutamine. Whereas the outcome of patients with nonviable myocardium but inducible ischemia was extremely poor, that of patients without inducible ischemia was good. We made very similar observations in our study. Indeed, the 3-year survival of our medically treated patients with nonviable myocardium was poor (43%) when ischemia was inducible at high doses of dobutamine, whereas it was much better in the absence of inducible ischemia (7 of 7 patients were alive after 3 years). Altogether, these data suggest that myocardial ischemia and viability probably need to be assessed in combination to fully appreciate the long-term prognosis of patients with chronic LV ischemic dysfunction. In daily clinical practice, this can be probably achieved by either of 3 methods: exercise-redistribution-reinjection thallium scintigraphy single photon emission computed tomography (SPECT), low- and high-dose dobutamine echocardiography, and rest fluorodeoxyglucose-PET imaging (because it can readily identify both viable and ischemically compromised myocardium).
Risk Stratification in Patients With LV Ischemic Dysfunction
This study categorized patients into subgroups with varying risks of death and used this information clinically. By combining the clinical variables retained in the initial Cox’s model with the information on myocardial ischemia and viability, it became possible to evaluate the risk of death in an individual patient and to determine whether he or she was likely to benefit from an intervention in terms of long-term outcome. For instance, the data indicate that patients with 1- or 2-vessel disease and LV dysfunction (55% of our study population) are unlikely to benefit from revascularization in the absence of viable or ischemic myocardium. In patients with more severe coronary disease, the data show that revascularization will always improve survival. The survival benefit is 3 to 4 times greater, however, in the presence of viable or ischemic myocardium.
Although the present study had a prospective design, for obvious ethical reasons, we did not randomly allocate patients to either medical treatment or revascularization. This decision was based on the fact that many of our patients had extensive coronary disease and a low ejection fraction. Therefore, we felt it was unethical to randomize treatment. Thus, we always proposed a revascularization procedure to the referring cardiologist and the patients. For various reasons, a significant number of patients did not undergo the proposed revascularization procedure, giving us the opportunity to examine the impact of ischemia and viability on the prognosis of medically treated patients as well. It should be stressed that the decision to treat medically was never based on the fact that the coronary vessels were inadequate for a revascularization procedure. Instead, we only selected patients whose coronary vessels were angiographically suitable for either PTCA or CABG and in whom the likelihood of complete revascularization was high. In addition, none of the patients suffered from potentially lethal noncardiac diseases that could have compromised their long-term prognosis. As a consequence of this selection procedure and despite the absence of randomization, most of the variables that were considered in the survival analysis were well balanced between the different patient subgroups. However, we cannot completely exclude the possibility that some unaccounted factors influencing selection for either treatment option nonetheless contributed to our results.
The present study indicates that, among the parameters commonly available in the preoperative assessment of patients with chronic LV ischemic dysfunction, the presence of diabetes, the extent of the underlying coronary artery disease, the treatment options, the presence of inducible ischemia (determined by thallium scintigraphy but not by dobutamine echocardiography), and the presence of viable myocardium (determined by both thallium scintigraphy and dobutamine echocardiography) are independently associated with subsequent mortality. These observations may be useful in determining which patients with impaired LV function are most likely to benefit from revascularization.
This work was supported in part by grant Action de recherche concertée n°96/01-199 and Fonds de recherche scientifique et médicale n°3.4540.95.
- Received August 7, 1998.
- Revision received April 21, 1999.
- Accepted April 22, 1999.
- Copyright © 1999 by American Heart Association
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