(Circulation. 1997;96:793-800.)
© 1997 American Heart Association, Inc.
Articles |
From the Cardiovascular Division, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Va.
Correspondence to Dr Michael Ragosta, Cardiovascular Division, Box 158, University of Virginia Health Sciences Center, Charlottesville, VA 22908. E-mail mragosta{at}virginia.edu
| Abstract |
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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.
Key Words: revascularization cardiomyopathy ischemia
| Introduction |
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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.
| Methods |
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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
Preoperative Data
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.
Late Follow-up
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.
Statistical Analysis
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
2 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.
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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
2 when a continuous factor is untransformed
(ie, assumes a linear relationship between the factor and the risk of
having an eventthe hazard and the
2 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
(
2=1.94, 3 df). For LVEF, the test
results were P=.793 (
2=1.04, 3
df). For the viability index, the test results were
P=.038 (
2=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.
| Results |
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Cardiac Catheterization
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.
201Tl Scintigraphy
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
(
2=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 (
2 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.
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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 ß-blockers (2 of 33 versus 8 of 33,
P=.08), the total number of patients discharged on
ß-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.
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| Discussion |
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Several studies from our group and others have shown that noninvasive techniquesincluding 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.
Clinical Implications
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.
Study Limitations
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.
Conclusions
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 |
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| Acknowledgments |
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Received November 5, 1996; revision received February 14, 1997; accepted March 2, 1997.
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G. L. Miller, I. L. Kron, and J. T. Cope Viability Assessment Before CABG • Response Circulation, September 29, 1998; 98 (13): 1350 - 1353. [Full Text] [PDF] |
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J. E. Udelson Steps Forward in the Assessment of Myocardial Viability in Left Ventricular Dysfunction Circulation, March 10, 1998; 97(9): 833 - 838. [Full Text] [PDF] |
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D Pagano, R S Bonser, J N Townend, F Ordoubadi, R Lorenzoni, and P G Camici Predictive value of dobutamine echocardiography and positron emission tomography in identifying hibernating myocardium in patients with postischaemic heart failure Heart, March 1, 1998; 79(3): 281 - 288. [Abstract] [Full Text] |
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