Ann Thorac Surg 1997;64:437-444
© 1997 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Influence of Left Ventricular Function on Survival After Coronary Artery Bypass Grafting
Elisabeth Ståhle, MD, PhD,
Reinhold Bergström, PhD,
Bo Edlund, MD,
Gunnar Frostfeldt, MD,
Bo Lagerquist, MD, PhD,
Ivar Sjögren, MD,
Hans Erik Hansson, MD, PhD
Departments of Thoracic and Cardiovascular Surgery, Cardiology, and Diagnostic Radiology, University Hospital, Uppsala, Sweden
Accepted for publication February 19, 1997.
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Abstract
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Background. Preoperative left ventricular function is a most important predictor for survival in patients with ischemic heart disease. To elucidate the optimal timing of recommended coronary artery bypass grafting, we investigated the influence of different aspects of preoperative left ventricular function on relative survival.
Methods. To calculate the relative survival and estimate the disease-specific survival, we compared 6,514 patients who survived the first month after primary coronary artery bypass grafting with the general Swedish population stratified by age, sex, and 5-year calendar period. In particular we studied the relation between relative survival and different aspects of left ventricular performance, namely left ventricular function at rest, New York Heart Association functional class, and number of previous myocardial infarctions.
Results. The three variables (left ventricular function at rest, New York Heart Association functional class, and number of previous myocardial infarctions) as well as age and follow-up year gave independent information concerning relative survival. The results from this multivariate analysis were used to define a risk score for each patient. Patients were categorized into different risk groups. Patients in the low-risk group (30% of the total) showed a survival better than that of the population at large for 9 years after operation. The medium-risk group had no or low excess mortality for about 7 years, and the high-risk group (25%) showed increased excess mortality immediately after operation.
Conclusions. If primary coronary artery bypass grafting is performed before the left ventricular function and physical performance deteriorate, survival is excellent.
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Introduction
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The present study investigates the impact of preoperative left ventricular performance on relative survival after primary coronary artery bypass grafting (CABG). Relative survival provides a measure of the excess mortality among CABG patients compared with mortality in the general population [1]. Particular questions addressed are the relation of the excess mortality to left ventricular function at rest [2], to New York Heart Association (NYHA) functional class [3] (hypothesized to reflect left ventricular function during exercise [4]), and to number of previous myocardial infarctions (hypothesized to relate to the occurrence of myocardial scarring as opposed to hibernating myocardium [5]). The independent influence of these aspects of left ventricular function, together with age at operation and follow-up year, on relative survival are analyzed in multivariate fashion.
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Material and Methods
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Patients
From January 1970 through June 1992, 6,742 patients underwent primary CABG without concomitant surgical procedures at the Department of Thoracic and Cardiovascular Surgery of the University Hospital, Uppsala, Sweden. There were 5,520 men (82%) (mean age, 59.2 years; range, 25 to 81 years) and 1,222 women (mean age, 61.5 years; range, 31 to 80 years). Of the total 6,742 patients, 5,443 (81%) had stable angina pectoris and 1,299 had unstable angina (recurrent episodes of angina at rest requiring hospitalization). Clinical data are presented in Table 1
. A total of 6,514 patients survived the first month and were included in the long-term analyses.
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Table 1. . Clinical Characteristics of Patients Undergoing Primary Coronary Artery Bypass Grafting, With the Operative Mortality Rates
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Operative and Postoperative Management
Standard surgical and myocardial protection methods were used [6]. The use of a left internal thoracic artery (ITA) graft became routine in 1985. The right ITA was used in 165 patients and a bilateral ITA procedure in 150 patients. Medication with antiplatelet drugs was recommended for at least 1 year postoperatively [6], but depended on the discretion of the referring cardiologist.
Data Collection and Follow-up
All clinical data, except those obtained on evaluation of preoperative angiograms in patients who underwent operation before 1987, were recorded prospectively and stored in a computer. Left ventricular (LV) function was classified as either normal, moderate dysfunction, or severe dysfunction, on the basis of the ejection fraction, information that was available in 4,569 patients (68%). In patients without objective data the grading was made by subjective evaluation by the radiologist. Ejection fraction values more than 0.50 were considered to represent normal LV function, values between 0.50 and 0.35 moderate LV dysfunction, and values less than 0.35 severe LV dysfunction.
The NYHA classification [3] of congestive heart failure was made on the basis of the preoperative interview with the patient. Patients who suffered slight discomfort with normal activities but were able to walk a mile at their own speed and could climb stairs slowly without undue discomfort were allocated to NYHA class IIIA. Patients who could manage only the lightest of activity without discomfort, were able to walk only short distances without resting, and had difficulty in going up stairs were allocated to NYHA IIIB. In addition, the number of previous infarctions was culled from medical records and electrocardiograms. Diabetes was defined as the occurrence of medication, oral or insulin. Hypertension was defined as antihypertensive medication or a blood pressure of more than 140/90 mm Hg before operation.
A unique 10-digit national registration number is allocated to every Swedish citizen. In January 1993 all patients were followed up with respect to survival by computerized linkage between two national registers, namely the Swedish Cause of Death Register and a continuously updated population register. By use of these combined registers, all patients could be assigned a date of death or identified as being alive on December 31, 1992. A second CABG was performed on 314 patients during the follow-up period.
Statistical Methods
Logistic regression analysis [7] was used to identify factors related to early mortality (death from any cause within 30 days postoperatively). Results are presented in the form of odds ratios. For the small absolute risks during the first 30 days, the odds ratio is very close to the relative risk. Identification of risk factors was based on stepwise analysis.
The observed survival rate for long-term mortality (death from any cause after 30 days postoperatively) was calculated by the actuarial (life table) method, and mortality related to ischemic heart disease was estimated by computing the relative survival rate, as the ratio of the observed to the expected rate [1, 8]. The expected survival rates were calculated from life tables compiled from the total population of Sweden stratified by sex, 5-year age group, and 5-year calendar period. The disease-specific annual death risk was computed as a complement of the annual relative survival (Fig 1).
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Fig 1. . Annual disease-specific death risk after primary coronary artery bypass grafting among patients who survived 30 days postoperatively (n = 6,514). The 95% confidence intervals for 1, 5, 10, and 15 years of follow-up are given. Also the disease-specific death risk (solid circle) based on all deaths during the first year is depicted with 95% confidence intervals.
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The multivariate analysis of observed survival was based on the Cox proportional hazards model [9]. Both the standard continuous proportional hazards model and a model based on grouped annual data were estimated and the explanatory variables were used in categorical or categorized form. The relative hazard exp(ßi) was used as a measure of the risk of death in different groups, where ßi is the basic parameter in the Cox model.
The following variables were entered into the Cox analyses of observed survival: demographic variables (age at operation, sex, year of operation), history of the disease (number of previous infarctions), symptoms and clinical status (stable versus unstable angina, dyspnea, duration of symptoms, left heart failure, NYHA functional class, hemodynamic instability), associated conditions (hypertension, diabetes, other serious diseases, eg, malignancies), preoperative catheterization data (number of diseased vessels, ie, with stenosis of 
50%; stenosis of the left main coronary artery of 50%; left ventricular function), and characteristics of the surgical procedure (ITA as a graft, number of distal anastomoses). Univariate analyses of relative survival were performed for the factors that gave independent information concerning observed survival in the Cox model together with the variable for use of ITA grafts.
The multivariate analyses considering both observed and expected numbers of deaths were based on a multiplicative model where the ratio between the observed and expected number of deaths (or corresponding death risks) was assumed to depend on the explanatory variables of age, NYHA class, LV function, number of previous infarctions, and follow-up year. The model was estimated by the maximum likelihood method on the assumption that the observed number of deaths had a Poisson distribution [10].
Grouped annual data from the first 10 years of follow-up were used with the categories shown in Tables 2 and 3.
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Table 2. . Basic Data Concerning Observed and Expected Deaths After 30 Days Based on Data From Follow-Up Years 1–10
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Table 3. . Multivariate Analysis of Relative Survival Using a Multiplicative Poisson Model Based on Data for the First 10 Years of Follow-up a
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On the basis of the results of the multivariate analysis presented in Table 3
, a risk score was computed for each patient. Patients were categorized according to the calculated risk score into a low-risk, medium-risk, or high-risk group. The cut-off points were chosen so as to get similar numbers in each group.
The grouped multivariate analysis of relative survival is less flexible than standard Cox estimation of observed survival. This necessitated a restriction in the number of variables included. Because our primary aim was to investigate the effect of myocardial performance, variables associated with this factor together with age and follow-up year were chosen.
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Results
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Early Mortality
The total early mortality rate was 3.4% (227 of 6,742 patients) (see Table 1). Female sex (odds ratio [95% confidence intervals] 1.9 [1.4 to 2.5]), advanced age at operation (60 to 70 years, 1.4 [1.1 to 1.9]; 70 years, 2.2 [1.5 to 3.2]), reduced LV function (moderate LV dysfunction, 1.4 [1.1 to 1.9]; severe LV dysfunction, 2.1 [1.4 to 3.3]), advanced NYHA functional class (class IIIB, 2.1 [1.5 to 2.9]; class IV, 2.8 [1.7 to 4.5]), three-vessel disease (1.6 [1.2 to 2.2 ]), and use of ITA grafts (0.5 [0.4 to 0.7]) were independently related to early mortality in the multivariate logistic regression model.
Late Mortality (Conclusions From Simple Descriptive Methods)
Observed and relative survival rates for all patients are depicted in Figure 2. Among those patients who were alive 30 days after operation, the relative survival rates after 5, 10, and 15 years were 99.5%, 89.4%, and 70.0%, respectively. Even when patients who died during the first month were excluded from the long-term analyses, there was a slight excess mortality during the first year of follow-up (see Table 2; Fig 1). During follow-up years 2 to 5 the annual disease-specific death risk was close to, or even lower than, zero. Starting with year 7, there was a rapid increase until year 10, when the annual disease-specific death risk was 4.5%. The excess risk remained at this level during the rest of the follow-up period for which meaningful calculations were possible (up to year 15). Table 2 shows the number of observed and expected deaths and confirms the results from the relative survival analyses.
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Fig 2. . Observed and relative survival after primary coronary artery bypass grafting in all patients (n = 6,742); 95% confidence intervals at 5, 10, and 15 years and the number ( N) of patients at risk at operation and after 5, 10, and 15 years are given.
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Analysis of individual prognostic variables showed that the relative survival improved with age (Fig 3). In the oldest age group the survival was markedly better than that in the general population, with a 10-year relative survival of 119%. In the second oldest age group the cumulative relative survival was more than 100% until the end of follow-up year 7.
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Fig 3. . Relative survival after primary coronary artery bypass grafting by age at operation in patients who survived the first postoperative month. The 95% confidence intervals at 5, 10, and 15 years and the numbers (N) of patients at risk are given.
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Good ventricular function implied better survival for 8 years compared with that in the general population (Fig 4). Patients with moderate dysfunction had excess mortality during the first year and subsequently virtually no excess mortality for about 4 years after operation. In patients with severe LV dysfunction the annual excess risk was about 3% to 4% starting in the year of operation. The effect of number of previous infarctions (Fig 5) was similar to the effect of LV function at rest. The few patients in NYHA functional class II showed better survival than the general population, with a 10-year relative survival of 103% (Fig 6). In functional class IIIA the cumulative relative survival was more than 100% during the first 6 years of follow-up.
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Fig 4. . Relative survival after primary coronary artery bypass grafting by left ventricular (LV) function at rest in patients who survived the first postoperative month. The numbers (N) of patients at risk are given.
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Fig 5. . Relative survival after primary coronary artery bypass grafting by number of previous infarctions in patients who survived the first postoperative month. The numbers (N) of patients at risk are given.
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Fig 6. . Relative survival after primary coronary artery bypass grafting by preoperative New York Heart Association (NYHA) functional class in patients who survived the first postoperative month. The numbers (N) of patients at risk are given.
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Patients with at least one ITA graft showed a tendency toward an increased number of years with minimal or no excess mortality, compared with those with vein grafts only (Fig 7). This tendency was not statistically significant.
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Fig 7. . Relative survival after primary coronary artery bypass grafting with use of grafts with veins only compared with grafts with at least one internal thoracic artery (ITA) in patients who survived the first postoperative month; 95% confidence intervals at 5 and 10 years and the numbers (N) of patients at risk after 1 month and after 5, 10, and 15 years are given.
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Late Mortality (Multivariate Analyses of Observed Survival)
The NYHA functional class, LV function, and number of infarctions were correlated, although this correlation was not strong (Spearman correlation coefficient for NYHA class versus LV function, 0.10; LV function versus number of infarctions, 0.34; NYHA class versus number of infarctions, 0.09).
In a multivariate Cox model, the observed survival was influenced independently by the following: age at operation (relative hazard [95% confidence interval]: 50 to 60 years, 1.4 [01.1 to 1.7]; 60 to 70 years, 1.7 [1.4 to 2.1]; 70 years, 2.8 [2.1 to 3.8 ]); NYHA functional class (class II, 0.5 [0.3 to 1.0]; class IIIA, 0.8 [0.7 to 1.0]); number of previous infarctions (two to three infarctions, 1.4 [1.2 to 1.6]; four or more infarctions, 2.1 [1.5 to 3.0]); impaired LV function (moderate LV dysfunction, 1.5 [1.3 to 1.8]; severe LV dysfunction, 2.4 [1.5 to 3.0]); three-vessel disease (1.3 [1.1 to 1.5]); year of operation (1980 to 1989, 0.6 [0.5 to 0.7]; 1990 to 1992, 0.4 [0.3 to 0.6]); diabetic disease (1.5 [1.2 to 1.8]); and hypertension (1.2 [1.1 to 1.4]). Use of ITA grafts did not significantly influence the observed survival (relative hazard 0.9 [0.8 to 1.1]).
Late Mortality (Multivariate Analyses of Relative Survival)
Table 3 shows the results of a modeling of the ratio between observed and expected number of deaths. There is very little difference between the multivariate model and the model with adjustment for follow-up year only. The rapid increase in the risk of death from about follow-up year 7 is less marked in the multivariate model, with relative risk values of 2.2 and 1.7 during follow-up year 10 (compared with the first year) in the two cases, respectively. Otherwise the results from the univariate relative survival analyses are confirmed. The variables NYHA class, ventricular function, and number of infarctions had strongly significant effects, with relative risks of 2.1 to 2.3 for the worst category compared with the best one in all three cases. There is a very large reduction in risk with age, relative risk in the highest age group being 0.2. The fit of the multivariate model is excellent (Pearson 
2 statistic 712.09 on 731 degrees of freedom).
When patients were categorized according to a risk score, the low-risk group showed a survival better than that of the population at large for 9 years. The medium-risk group had no or low excess mortality for about 7 years and in the high-risk group the annual excess risk was about 2% to 3% starting in the year of operation (Fig 8).
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Fig 8. . Relative survival after primary coronary artery bypass grafting by risk group based on a hazard calculated from left ventricular function at rest, New York Heart Association functional class, number of infarctions, and age in patients who survived the first postoperative month; 95% confidence intervals at 5 and 10 years and the numbers (N) of patients at risk after 1 month and after 5 and 10 years are given.
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Comment
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In this study we used as our control the expected survival of the Swedish population. The survival rates of the patients were similar to the normal expected survival of an age- and sex-matched group in the general population for about 6 years after the first CABG. Subsequently, the annual extra disease-specific mortality risk increased, but it tended to stabilize at around 5% after the tenth year. This confirms the previous long-term observations after CABG that the beneficial effects of operation appear to decline with time [6, 11]. This is especially true for patients who have received predominantly vein grafts [6, 11–13]. However, we found that deaths from cardiac disease related strongly to the LV performance at the time of operation. Patients with unimpaired LV function at rest and physical performance and who had sustained no more than one myocardial infarction showed low excess mortality for several years after operation. The study results underline the excellent disease-specific survival after CABG if operation is undertaken before the LV function deteriorates.
We were not able to verify the previous findings of improved survival as the result of use of ITA as a graft [12, 13], but did find a tendency toward such an effect. In a previous study we noted that use of ITA grafts improved survival in patients with LV aneurysm [14].
A number of factors must be considered when relative survival [1, 15, 16] is being used. First, in calculations of the expected survival in the study group it has to be assumed that the survival in the general population is unaffected by deaths related to the disease under study. However, deaths from ischemic heart disease are common in the general population. Second, patients being considered for CABG are selected with respect to their better overall medical condition concerning noncardiac diseases at the time of operation. This is probably especially true in the older age groups and would increase their relative survival rate. Moreover, the present study is focused on the prognosis in patients surviving the immediate postoperative period. Exclusion of deaths within the first month also biases the results in favor of operation. If deaths within the first 30 postoperative days are considered (n = 227), the number of deaths during the first postoperative year will be 361 as compared to the 99.5 expected. Therefore, there is a risk that studies of relative survival rates, including the present one, will underestimate the excess mortality rates after cardiac operations. This consideration, again, is especially valid concerning the oldest age groups, who have the highest operative mortality. If deaths occurring within the first postoperative month were considered, the survival benefits of these age groups as compared to the survival of corresponding age groups in the general population would be reduced.
In our multivariate analyses we report results from a basically multiplicative Poisson model, which means that the excess mortality is obtained by modeling of the ratio of the observed to the expected death risk. The regression model most closely connected with relative survival as used in the descriptive analyses is the mixed additive–multiplicative model that was previously used by our group [6, 17]. Here the excess (disease-specific) mortality is modeled additively as the difference between the observed death hazard and the hazard expected in the comparison group from the general population. In cases such as the present one, when the excess mortality defined in this way is very small, sometimes even negative, the mixed additive–multiplicative model becomes doubtful. This may be seen as a failure to obtain estimates or as difficulties in obtaining such estimates. We managed to obtain estimates, and qualitatively these led to the same conclusions as those that can be drawn from Table 3. The different specifications mean that they are not quantitatively comparable. A more detailed discussion of the models considered can be found in references 6, 17, and 18.
Left ventricular function is a major predictor for the long-term results of CABG [6, 11, 12]. Echocardiography [2] and left ventriculography [2] provide objective and reproducible measures of the LV function at rest. However, it is a weakness that NYHA functional class had to be used as a surrogate measurement for LV function under stress [3, 4]. Furthermore, the number of myocardial infactions was used as a surrogate measurement of myocardial scarring to differentiate between myocardial fibrosis or hibernation [2, 5]. However, NYHA class and number of infarctions were available in all patients and at least theoretically, may well reflect different aspects of LV performance. Multivariate analyses confirmed that LV function, NYHA class, and number of previous infarctions together with age and follow-up year gave independent information concerning relative survival (ie, each variable provided additional prognostic information). With the aim of illustrating the amount of extra prognostic information obtained from this combination of variables as compared to each of them used alone, a risk score was calculated from the multivariate estimates and patients with different prognoses identified. The patients with the best prognosis had excellent relative survival for many years after the first CABG, whereas those with the worst prognosis showed increased mortality starting immediately after operation.
In conclusion, this study confirms that if primary CABG is performed before the LV function and physical performance deteriorate, survival is excellent. However, the results do not provide support for an early and aggressive surgical appproach in all patients presenting with ischemic heart disease, and normal or near normal LV function. The present study was based on patients with severe or moderate angina pectoris, in whom the major reason for CABG was to provide relief of symptoms and improved physical performance. For patients with mild or no angina (ie, silent ischemia), other considerations are needed. For example, the Coronary Artery Surgery Study [19] showed that in patients with mild angina and intact LV function, CABG could safely be delayed until more severe symptoms occurred. For patients with impaired LV function, it should also be recognized that, although they have an increased surgical risk, a CABG-related improvement in survival is more likely to occur the worse the LV function is [11]. The question of optimal timing of CABG is complex and necessitates intergration of a great number of factors, several of which are not considered in the present study.
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Footnotes
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Address reprint requests to Dr Ståhle, Department of Thoracic and Cardiovascular Surgery, University Hospital, S-751 85 Uppsala, Sweden.
This article has been selected for the open discussion forum on the STS Web site: http://www.sts.org/annals
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Abstract
Introduction
