Improved Outcome After Coronary Bypass Surgery in Patients With Ischemic Cardiomyopathy and Residual Myocardial Viability
Background Although residual myocardial viability in patients with coronary artery disease and extensive regional asynergy is associated with improved ventricular function after coronary bypass surgery, the relationship between viability and clinical outcome after surgery is unclear. We hypothesized that patients with poor ventricular function and predominantly viable myocardium have a better outcome after bypass surgery compared with those with less viability.
Methods and Results Seventy patients with multivessel coronary artery disease and left ventricular ejection fractions <40% who underwent preoperative quantitative 201Tl scintigraphy before coronary bypass surgery were analyzed retrospectively. 201Tl scintigrams were reviewed blindly, and each segment was assigned a score based on defect magnitude. Segmental viability scores were summed and divided by the number of segments visualized to determine a viability index. The viability index was significantly related to 3-year survival free of cardiac event (cardiac death or heart transplant) after bypass surgery (P=.011) and was independent of age, ejection fraction, and number of diseased coronary vessels. Patients with greater viability (group 1; viability index >0.67; n=33) were similar to patients with less viability (group 2; viability index ≤0.67; n=37) with respect to age, comorbidities, and extent of coronary artery disease. There were 6 cardiac deaths and no heart transplants in group 1 patients and 15 cardiac deaths and two transplants in group 2 patients. Survival free of cardiac death or transplantation was significantly better in group 1 patients on Kaplan-Meier analysis (P=.018).
Conclusions We conclude that resting 201Tl scintigraphy may be useful in preoperative risk stratification for identification of patients more likely to benefit from surgical revascularization.
Improvement in ventricular dysfunction may occur after acute myocardial infarction or after revascularization in patients with chronically hypoperfused viable myocardium.1 2 3 4 5 6 7 8 Clinical variables, such as the presence of angina pectoris, absence of Q waves, and severity of asynergy, are unreliable for establishing the presence of viability. Several noninvasive imaging techniques are useful for differentiating viable from nonviable myocardium and for identifying zones with reversible asynergy.9 10 11 12 13 14 15 16 17 18 19 20 Determining viability in areas of myocardium with severe regional dysfunction may be particularly important in patients with severe LV dysfunction and multivessel CAD in whom CABG is contemplated. Results of large registries and randomized trials comparing coronary bypass surgery and medical therapy have suggested improved survival in patients with reduced LVEF and multivessel CAD treated with surgery.21 22 23 24 25 26 27 However, such patients have increased surgical risk and lower operative and long-term survival rates than those with better ventricular function.22 Whether a subgroup of patients with ischemic cardiomyopathy and multivessel CAD who do not substantially benefit from surgery exists, despite arteries suitable for grafting, is not known.
We and others have previously shown that patients with an EF <35% and multivessel CAD may have improved regional and global LV function 8 weeks after surgery if there is substantial residual viability on resting 201Tl scintigraphy.9 10 Nevertheless, the link between residual viability and improved clinical outcome after coronary bypass surgery in patients with ischemic cardiomyopathy is unclear. Accordingly, we tested the hypothesis that patients with low EF, multivessel CAD, and a greater degree of myocardial viability on rest-redistribution 201Tl scintigraphy would have a better outcome after CABG compared with patients with a comparable extent of CAD and reduced LVEF but less viability.
Between January 1, 1990, and March 1, 1995, 210 patients underwent resting 201Tl scintigraphy for clinical assessment of myocardial viability; 92 of these were subsequently referred for CABG. Among these 92 patients, 8 had EFs ≥40%, 6 had prior CABG, and 5 had coexisting valvular disease and underwent concurrent aortic (n=3) or mitral (n=2) valve replacement. Three patients had single-photon emission computed tomography imaging and were excluded. The study group consisted of the 70 remaining patients with EFs <40% without significant valvular disease who were referred for a first coronary bypass surgery and underwent preoperative quantitative planar 201Tl imaging for viability determination. A detailed analysis regarding changes in ventricular function 8 weeks after surgery in 21 of these patients was previously reported.9
Clinical Data Collection
Clinical data were collected retrospectively by chart review by use of predetermined definitions and a standardized data collection form. Investigators were blinded to postoperative outcome and extent of preoperative myocardial viability. The preoperative ECG was blindly interpreted for rhythm, left bundle-branch block, and the presence of pathological Q waves. Hemodynamic data from preoperative cardiac catheterization were collected. Coronary angiograms were reviewed without knowledge of patient outcome, and the number of coronary arteries with >50% stenosis on coronary angiography was determined. LVEF was determined by ventriculography in 58 patients, by equilibrium-gated radionuclide angiography in 8 patients, and by echocardiography in 4 patients.
Operative and Early Postoperative Data
Coronary bypass surgery was performed by use of cold cardioplegia and potassium arrest. The conduit type (saphenous vein versus internal mammary artery) and distal insertion site of all bypass grafts were noted. Cardiopulmonary bypass and aortic cross-clamp times were obtained from the operative report. The performance of additional procedures such as placement of an implantable defibrillator or an IABP was noted. The postoperative course was also reviewed. The length of time that inotropic agents were used, the time to extubation, the number of days in the intensive care unit, hospital length of stay, and total hospital costs were determined. Survival to hospital discharge was determined, and medications at the time of hospital discharge were recorded.
Survival status was determined by contacting all patients or next of kin by telephone. The cause of death was established by attending physician interview, review of hospital records, or death certificate. Cardiovascular deaths were defined as death from stroke, acute myocardial infarction, and refractory congestive heart failure and any sudden, unexplained death. Cardiac events during late follow-up were defined as cardiac death and cardiac transplantation for refractory heart failure.
Rest-Redistribution 201Tl Scintigraphy
Preoperative quantitative 201Tl scintigraphy was performed after an overnight fast. In 65 patients, resting imaging was performed 10 minutes and 3 hours after injection of 2.0 to 3.0 mCi of 201Tl as described previously9 28 29 ; 5 patients underwent only delayed rest imaging at 3 hours because of clinical instability. Planar images were obtained in the anterior and 45° and 70° left anterior oblique projections. The lung/heart uptake ratio was calculated as previously described.28 29
Quantitative scintigraphic images were blindly interpreted by two experienced observers without knowledge of patient identity. Disagreements were handled by a third reader, with consensus reached among the three observers. The three planar images were divided into 15 segments.9 On initial images, segments were classified as demonstrating either normal uptake (>75% of peak uptake), a mild defect (50% to 75% of peak uptake), or a severe defect (<50% of peak uptake). Delayed images were quantitatively assessed for the presence of partial or complete redistribution as described previously.9 28 In the 5 patients who underwent only delayed imaging, segments were quantitatively assessed and classified in the same manner as the initial images.
Resting 201Tl scintigrams were scored as follows. Segments with normal initial uptake or those with a defect of any magnitude showing complete redistribution were classified as showing “normal viability” and assigned a score of 2. Segments with a mild persistent defect or partial redistribution such that 201Tl uptake on the delayed image reached >50% (but <75%) of maximum 201Tl uptake were classified as showing “mildly reduced viability” and assigned a score of 1. Segments with severe defects and either no redistribution or partial redistribution such that the uptake on the delayed image was <50% of maximum uptake were classified as showing “severely reduced viability” and assigned a score of 0. Previous investigations have shown the importance of a 50% uptake obtained with quantitative analysis for discriminating viable and nonviable segments.30 31 32 In the five patients with only delayed rest images, segments were scored as 2, 1, or 0 if they showed normal perfusion, a mild defect, or a severe defect, respectively. Because the maximal possible viability score was 30, the viability scores were summed and divided by 30 to yield a viability index.
All normally distributed data were expressed as mean±SD; data not normally distributed were expressed as median (25th and 75th percentiles). For descriptive purposes, the viability index was divided at the median, creating a group of greater viability (greater than the median) and one of lesser viability (equal to or below the median). Tables of baseline clinical and angiographic characteristics are presented by the two levels of viability. Secondary operative and postoperative outcomes are similarly presented. Comparisons between the two viability groups were performed and group differences of continuous factors were compared by use of Wilcoxon signed rank tests. Group differences of categorical variables were compared by use of χ2 tests or, in the cases of small cell sizes, Fisher’s exact test. All probability values are from two-sided tests. For Tables 1⇓ and 2⇓, the probability values will be used to show which variables are unbalanced across levels of viability score and will thereby require inclusion as adjustment factors in the primary outcomes model. Because the outcomes in Table 3⇓ are secondary outcomes for this study, probability values for the table should be considered hypothesis generating rather than conclusive in nature.
The late cardiac end point was defined as cardiovascular death or cardiac transplantation. The effect of the viability index and other potential prognostic factors on this outcome was evaluated by use of Cox proportional hazards modeling techniques.33 One of the assumptions made in using this type of model is that the instantaneous risk (or hazard) of suffering the event is proportional across all values of the independent risk factor. One method of evaluating the appropriateness of this assumption is the use of restricted cubic splines.34 Very briefly, cubic splines divide the predictor variable into quantiles. The shape of the relationship between the variable and the outcome can then vary from quantile to quantile. In this way, one can fit a wide range of shapes for the relationship between outcome and predictor, not restricting the shape to follow a straight line. One can estimate the extent to which the relationship deviates from linear by comparing the model χ2 when a continuous factor is untransformed (ie, assumes a linear relationship between the factor and the risk of having an event—the hazard and the χ2 when the factor is modeled by use of a restricted cubic spline). We used this method of comparison to evaluate the need for transformations of age, LVEF, and viability index when modeling event-free survival. For age, the test for a need for nonlinearity terms gave P=.577 (χ2=1.94, 3 df). For LVEF, the test results were P=.793 (χ2=1.04, 3 df). For the viability index, the test results were P=.038 (χ2=8.42, 3 df). Therefore, it appears that it is appropriate to model both age and LVEF as linear terms and that the viability index is modeled as a nonlinear variable with knot points at 0.47, 0.60, 0.67, 0.77, and 0.87.
The study cohort consisted of 70 patients (54 men, 16 women) with a median age of 66 years (range, 59 to 71 years). Prior myocardial infarction, defined as remote or occurring before the index hospital admission, was present in 40 of 70 patients (57%). Significant comorbidities were present in many patients, including hypertension (35 of 70; 50%), diabetes mellitus (25 of 70; 36%), pulmonary disease (18 of 70; 26%), cerebrovascular disease (12 of 70; 17%), and renal insufficiency (7 of 70; 10%). Myocardial infarction was the presenting syndrome in 35 patients (50%), of which 20 were of non–Q-wave type and 15 were of the Q-wave type. In 10 patients, there was no known clinical history of myocardial infarction, either in the past or on presentation. Stable (n=14) or unstable (n=16) angina was present in 30 additional patients; 5 patients had no chest pain (infarction or angina) at presentation. Congestive heart failure (defined as the presence of significant rales on exam with associated dyspnea or pulmonary congestion on chest roentgenogram) was a presenting feature in 40 of 70 patients (57%). Thirteen other patients had a history of congestive heart failure but did not present with heart failure as defined above. Thus, 53 of 70 patients (76%) had evidence of preoperative congestive heart failure. Four patients required insertion of an IABP preoperatively because of congestive heart failure (n=2) or severe and uncontrolled anginal symptoms (n=2).
At cardiac catheterization, significant LV dysfunction was present at rest with a mean PCWP of 22±9 mm Hg and a mean LV end-diastolic pressure of 25±9 mm Hg. The mean LVEF was 0.28±0.06, and coronary arteriography demonstrated significant stenosis (>50%) of two major epicardial vessels in 17 patients and three major epicardial vessels in 53 patients.
Significant lung uptake at rest, defined as a maximum lung/maximum heart uptake ratio of >0.50 on the initial anterior view image, was present in 64 of 70 patients (91%) with the mean maximum lung/maximum heart uptake ratio of 0.64±0.13. For the entire cohort, each patient demonstrated an average of 7.9±2.4 segments with normal perfusion, 1.1±1.5 segments with a defect with complete redistribution, 2.5±2.5 segments with partial redistribution, and 2.6±2.1 segments showing a severe persistent defect. The mean viability index was 0.68 for the entire cohort, with a median viability index of 0.67 (0.60 to 0.80).
Early Postoperative Outcome
There were four in-hospital deaths resulting in an early postoperative mortality of 5.7%. In 3 patients, death was due to refractory congestive heart failure and inability to wean inotropic support, and in 1 patient, sudden death occurred on postoperative day 6 after an otherwise uneventful postoperative course. The mean viability index among the four patients with early death was 0.55±0.09 compared with 0.69±0.13 among the 66 patients with survival to hospital discharge (P<.05).
Late Postoperative Outcome
Among hospital survivors, the median time to follow-up was 1177 days (range, 590 to 1826). Nineteen additional deaths occurred during follow-up, and 2 patients underwent cardiac transplantation. Thus, including the 4 deaths in the early postoperative period, there were a total of 23 deaths and two cardiac transplants. Two deaths were due to noncardiac causes (one from homicide and one from metastatic vulvar carcinoma). Of the 21 remaining deaths, 10 resulted from refractory congestive heart failure, and 11 were sudden cardiac deaths.
When the viability index was plotted against the 3-year probability of survival free of cardiac event, the lowest likelihood of 3-year survival was seen among patients with a viability index between 0.55 and 0.70, with little additional risk apparent between 0.40 and 0.55 and no change in risk beyond an index of 0.80 (Fig 1⇓). With a Cox proportional hazards model in which the viability index is modeled as a nonlinear term, the viability index was found to be predictive of freedom from cardiac death or transplant (χ2=13.02, 4 df; P=.011). When the variables of age, LVEF, and number of diseased coronary vessels were entered into a multivariable Cox model, only the viability index contained significant independent prognostic information, with a strong trend toward age affecting outcome (χ2 for viability index=13.79, P=.008; for age, P=.094; for EF, P=.844; and for two versus three diseased vessels, P=.548). When backward stepwise techniques were used to see which factors together add significant prognostic information, only the viability index remained in the model. Therefore, none of the other three variables (age, EF, and number of diseased vessels) added significant prognostic information beyond that provided by the viability index.
Comparison of Patients With Greater and Lesser Viability
For the purpose of descriptive convenience, the group was divided into two groups based on the median viability index of 0.67. Thus, roughly half the patients have a viability index greater than the median viability index and have a greater extent of residual viability (group 1; n=33), and roughly half the patients have a viability index less than or equal to the median value and have lesser degrees of viability (group 2; n=37). Table 1⇑ compares the various patterns of defect severity and the number of patients with defects in multiple vascular territories among the two groups. As would be expected, group 1 patients had significantly more segments with normal perfusion and significantly fewer segments with severe persistent defects than group 2 patients (P=.0001). In addition, group 1 patients consisted predominantly of patients with defects in a single vascular territory (15 of 33 versus 3 of 37 group 2 patients, P=.001), whereas group 2 had a higher proportion of patients with defects in three vascular territories (14 of 37 compared with 3 of 33 group 1 patients, P=.005).
The baseline clinical characteristics of these two groups are compared in Table 2⇑. No statistically significant differences were found between groups 1 and 2 with respect to age, male sex, prior infarction, hypertension, or diabetes mellitus or cerebrovascular, pulmonary, or renal disease. There was no difference between the groups in terms of the proportion presenting with acute infarction, stable or unstable angina, or congestive heart failure. More patients with less viability (group 2) had Q waves (26 of 37 [70%] versus 15 of 31 [48%]), but this difference was not statistically significant. The mean EF was 0.29±0.06 for group 1 versus 0.27±0.06 for group 2 (P=.13). No differences in mean PCWP, LV end-diastolic pressure, mean right atrial pressure, or pulmonary artery pressures were observed between the groups. The extent of CAD was similar, with a median of three diseased arteries observed in both groups. Patients with less viability had a greater degree of lung 201Tl uptake compared with patients with more viability (0.68±0.14 versus 0.59±0.11, P=.005).
No group 1 patients died before hospital discharge, whereas four group 2 patients died in the early postoperative period (P=.12). No significant differences existed between the two groups with respect to median number of grafts, proportion of patients with internal mammary conduits, aortic cross-clamp and cardiopulmonary bypass times, proportion with automatic implantable cardiac defibrillators placed, number of hours until extubation, number of hours of pressor use, length of intensive care unit stay, hospital length of stay after bypass surgery, or total costs. The two groups did not differ with respect to the proportion discharged on diuretics, ACE inhibitors, or digoxin. Although there appeared to be fewer patients in group 2 discharged on β-blockers (2 of 33 versus 8 of 33, P=.08), the total number of patients discharged on β-blockers was quite small (10 of 66 or 15%). Table 3⇑ summarizes the important details of the operative and early postoperative courses in the two groups.
There were 6 cardiac deaths and no cardiac transplants in patients with more viability (group 1); 5 deaths were sudden, and 1 was due to refractory congestive heart failure. There were 15 cardiac deaths and two cardiac transplants in patients with less viability (group 2); 9 were due to refractory congestive heart failure, and 6 were sudden cardiac deaths. Thus, six end points (cardiac death or heart transplantation) occurred in group 1 patients compared with 17 in group 2 patients. Fig 2A⇓ shows the Kaplan-Meier event-free survival analysis. Patients with more viability had a significantly better event-free survival than those with less viability by Mantel-Cox statistics (P=.019). The cohort was divided by the median EF (0.28), and Kaplan-Meier curves generated for the two groups to illustrate that freedom from cardiac events were not significantly affected by EF (Fig 2B⇓). For the 25th and 75th percentiles of EF (0.21 and 0.33, respectively), the expected survival rates at 1 year were 84% (68% and 93%) versus 87% (75% and 94%) and at 3 years were 70% (50% and 84%) versus 74% (59% and 84%), demonstrating that event-free survival across levels of EF below 0.40 is similar. EF as a continuous variable to include its full prognostic information resulted in a value of only P=.696 for the prediction of cardiac events.
Despite increased surgical risk and higher long-term mortality rates than patients with better ventricular function, patients with low LVEF and multivessel CAD undergoing surgical revascularization have improved outcome compared with those treated medically on the basis of published registry studies and randomized trials.21 22 23 24 25 26 27 Given that long-term mortality in this group is still significant,22 it is possible that these patients can be further stratified for surgical risk and long-term prognosis by assessing the extent of viability in hypocontractile myocardium. On one end of the spectrum are patients with predominantly viable but hibernating myocardium who would be expected to benefit most from revascularization; at the other end are patients whose ventricular dysfunction is due predominantly to infarcted and nonviable myocardium and are less likely to benefit from surgical revascularization. The latter group may be better managed medically or with heart transplantation.
Several studies from our group and others have shown that noninvasive techniques—including rest-redistribution 201Tl scintigraphy,9 10 24-hour delayed 201Tl imaging,11 12 201Tl reinjection,13 14 dobutamine echocardiography,15 16 PET,17 18 99mTc isonitrile (99mTc sestamibi),19 and myocardial contrast echocardiography20 —are useful for demonstrating residual myocardial viability and predicting improvement in global and regional myocardial function after revascularization in patients with low LVEFs and significant CAD. However, data relevant to the relationship between prerevascularization viability patterns and clinical outcome after CABG are scanty.
Most of the studies addressing outcome and viability in patients with low LVEF have concentrated on differences in survival for patients treated medically compared with those treated surgically. The nonrandomized studies using rest-redistribution 201Tl scintigraphy35 36 and PET36 37 38 39 have suggested that patients with viability might have improved outcome when treated with surgical revascularization compared with patients treated medically. No study has yet determined whether the extent of viability alone is a significant variable predictive of operative and late clinical outcome in a group of patients undergoing surgical revascularization.
Importance of Results
This study has important implications about the role of viability assessment in the management of patients with low LVEF and multivessel CAD. First, our data suggest that patients with more viability on resting 201Tl scintigraphy have a better in-hospital outcome after CABG than patients with less viability. The mean viability index was significantly lower among patients with perioperative death compared with patients who survived to hospital discharge. In addition, there was a trend toward higher early mortality in patients with less viability.
More importantly, this study also supports the hypothesis that the extent of preoperative myocardial viability is a determinant of long-term outcome. The viability index was the only independent predictor of 3-year survival free of a cardiac event. The variables of age, LVEF, and number of diseased coronary vessels did not provide independent prognostic information and added no value to the viability index. Patients with a greater extent of viability on resting 201Tl scintigraphy had better long-term, event-free survival than patients with lesser degrees of viability. Those patients with lesser amounts of viability who underwent revascularization had a very high event rate at long-term follow-up, implying that their outcome may be no better than that seen in patients with low EF who were treated medically.22 It is important to note that in our study, patients with greater viability and those with less viability were virtually indistinguishable with respect to the clinical variables useful for prognostication in patients with CAD. Our data are consistent with previous observations that improvement in heart failure symptoms occurs in many patients who undergo CABG.40 41 42 43 More recently, it was reported that patients with ischemic cardiomyopathy and predominantly viable myocardium as assessed by PET were more likely to have improvement in heart failure symptoms and functional status.43 No long-term mortality data were reported in this study, and the cohort comprised only 36 patients.
The goal of the present study was to explore the conceptual link between viability and long-term outcome and not to provide scintigraphic guidelines for the often difficult clinical decision of selecting patients with poor EF for coronary bypass surgery. Care must be taken in extrapolating these results to clinical practice. Nevertheless, these results suggest that patients with nonviable myocardium have a higher operative mortality and poorer long-term outcome than those who have viable myocardium. Future prospective studies might be helpful in providing more specific guidelines to assist in clinical decision making.
Retrospective studies like this have several limitations. First, our study is biased in that it is not representative of the entire pool of patients with low LVEF referred for CABG because those with poor LV function and minimal viability might not have been referred for surgery. In addition, our study included a large proportion of patients presenting with an acute coronary syndrome, either unstable angina or acute myocardial infarction, and a significant number presenting in congestive heart failure. These patients may be at increased risk for both short- and long-term complications after CABG. Although it may be difficult to extrapolate our findings to all patients with poor ventricular function undergoing CABG, the present study does apply to a significant proportion of such patients. A second limitation is the use of different techniques to assess preoperative EF. This introduces considerable variability, making it difficult to discern differences between the groups. Although we did not detect a statistically significant difference in EF, a trend toward a lower EF in the group of patients with less viability was observed, and our sample size does not have the power to ensure that this difference is not significant. Nevertheless, EF was not related to survival as a continuous variable and provided no independent prognostic information in our statistical model, suggesting that in this population, long-term outcome was better predicted by viability than by EF. A third limitation is that variables that we did not assess, such as quality of the distal vessels and adequacy of revascularization, might be different between the groups and that these might have accounted for the difference in survival. Finally, data regarding changes in ventricular function after surgery were not available; thus, we were unable to correlate improvement in LVEF to long-term outcome, which would further strengthen the link between viability and outcome in patients with ischemic cardiomyopathy.
The present study shows that patients with low EF, multivessel CAD, and greater extent of viability on preoperative rest-redistribution 201Tl scintigraphy have better short- and long-term outcome after CABG than similar patients with lesser amounts of viability. These data suggest that the extent of viability in patients with ischemic cardiomyopathy is an important predictor of long-term prognosis after coronary bypass surgery.
Selected Abbreviations and Acronyms
|CABG||=||coronary artery bypass grafting|
|CAD||=||coronary artery disease|
|IABP||=||intra-aortic counterpulsation balloon pump|
|PCWP||=||pulmonary capillary wedge pressure|
|PET||=||positron emission tomography/tomographic|
We wish to express our gratitude to Jerry Curtis for his assistance in the preparation of this manuscript, to Karen S. Pieper, MS, for statistical assistance and review of our manuscript, and to our surgical colleagues for their cooperation and support.
- Received November 5, 1996.
- Revision received February 14, 1997.
- Accepted March 2, 1997.
- Copyright © 1997 by American Heart Association
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