Ann Thorac Surg 2001;72:1535-1541
© 2001 The Society of Thoracic Surgeons
Original article: cardiovascular
Better ischemic event-free survival after two internal thoracic artery grafts: 13 years of follow-up
Eric Berreklouw, MD, PhD*a,
Phillip P.C. Rademakers, MDa,
Jurgen M. Koster, MDa,
Linda van Leur, RNa,
Brigitte J.W. van der Wielen, RNa,
Paul Westers, PhDb
a Division of Cardio-thoracic Surgery, Catharina Hospital, Eindhoven, The Netherlands
b Centre for Biostatistics, University of Utrecht, Utrecht, The Netherlands
Accepted for publication June 22, 2001.
* Address reprint requests to Dr Berreklouw, Division of Cardio-thoracic Surgery, Catharina Hospital, PO Box 1350 5602 ZA Eindhoven, The Netherlands
e-mail: eberr{at}csi.com
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Abstract
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Background. We researched our data to determine whether pedicled bilateral internal thoracic artery (BITA) grafting led to better ischemic event-free survival compared to single ITA grafting, at 10 years mean follow-up.
Methods. Retrospectively 249 patients with BITAs with or without additional vein grafts (BITA group) were matched with 233 comparable patients with left ITA and additional vein grafts (LITA group), at a mean follow-up interval of 10 years.
Results. At 13 years, 76.2% ± 5.9% of the BITA and 78.3% ± 3.8% of the LITA patients were still alive (p = not significant). Death, recurrent angina, new myocardial infarction, or coronary reinterventions occurred more often in LITA (49.4%) than BITA (33.3%) patients (p = 0.0004). The ischemic event-free survival estimates for BITA patients (47.5% ± 8.4%) was better than for LITA patients (35.4% ± 5.1%) (p < 0.001). Multivariate analysis showed that BITA was a predictor for ischemic event-free survival (p = 0.0005).
Conclusions. For the decision to use one or two ITAs the positive influence of BITA grafting on ischemic event-free survival is more important than its effect on survival, per se. Compared to the general strategy of BITA grafting, neither total arterial revascularization nor the specific vessels grafted with BITA is relevant for the ischemic event-free survival.
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Introduction
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In treating patients with coronary artery disease the goal should be to approach a coronary event-free survival similar to that of a matched population without coronary artery disease. Although survival is of primary importance, other disabling consequences from coronary artery disease, like angina, myocardial infarction, and coronary reinterventions are equally important as long as one is still alive. To determine the best therapeutic option for a specific patient with coronary artery disease, the ischemic event-free survival associated with these options should be considered. It has been shown that coronary bypass grafting results in superior outcome compared to percutaneous coronary angioplasty (PTCA) in large subsets of patients with coronary artery disease [1]. Once the decision is made to operate, the surgeon should be aware that long-term event-free survival after coronary artery bypass grafting is not only related to the preoperative status of the patient and the progression of atherosclerotic disease in the native coronary arteries, but is also dependent on the patency of the bypass conduits used [2]. Already in 1986, it has been shown that the pedicled left internal thoracic artery (LITA) in comparison with the saphenous vein, has a superior patency and leads to a better survival after 10 years [3]. The LITA is now widely accepted as the standard conduit for revascularization of the left anterior descending artery. It took a longer time to prove additional benefit of using both pedicled internal thoracic arteries (BITA). Only very recently, investigators from the Cleveland Clinic were able to show that BITA grafting results in less death, reoperation, and PTCAs than LITA grafting, in a large series of patients with a mean follow-up of 10 years [4]. In a previous study of our group, we could not demonstrate any difference in outcome between LITA and BITA patients [5]. However, the median duration of follow-up in both patient cohorts in that study was relatively short (60 and 62 months, respectively) and the sample size relatively small (139 patients in each study group). The objective of this study was to reinvestigate the outcome of both surgical options in a larger study population with a longer duration of follow-up.
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Material and methods
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To obtain cohorts with substantial duration of follow-up, 249 consecutive hospital survivors, who were operated between February 1985 and December 1990 with the use of bilateral pedicled ITAs with or without additional vein grafts (BITA group) were, in a retrospective fashion, matched with 233 comparable patients, who were operated with one pedicled LITA and additional vein grafts (LITA group). The first 143 patients in each study group were investigated and described earlier by us [1]. More consecutive similar patients were added to obtain a larger sample size with sufficient follow-up. To focus on the long-term results, we included hospital survivors only, after we have shown that the hospital mortality of the first 100 of these patients was low, and similar in both study groups [2]. Patients with free ITAs, gastroepiploic arteries, reoperations, or combined procedures, were excluded from the study, as well as patients operated for an impending acute myocardial infarction. The number of free ITA and gastroepiploic artery grafts in this study period was relatively small, therefore we did not want to mix their results with those of pedicled ITA grafts. The patients were matched by hand to the following criteria: time of operation (next consecutive patient), age, sex, and extent of coronary artery disease. Depending on the preference of the surgeon, patients underwent BITA or LITA grafting. In all operated patients, a pedicled ITA was used as a single or sequential graft. In the LITA group, the LITA was anastomosed to the left anterior descending artery, its branches, or both. In the BITA group, the right ITA (RITA) was anastomosed to the left anterior descending artery, circumflex artery, or right coronary artery, their branches, or both. For the details of our operative techniques we refer to an earlier publication by our group [6]. Recurrent angina was defined as angina Canadian Cardiology Society class II or more during follow-up. An electrocardiographic stress test or thallium stress test was performed by preference of the referring cardiologist on an elective basis, or on the basis of symptoms, or a combination of these two.
Data collection and statistical methods
The charts and follow-up reports of the patients, as sent to us by the referring cardiologists, were reviewed by our surgical residents or research nurses between January and June 2000. If no recent follow-up report was available, the referring cardiologist or patient was contacted. Follow-up data could be obtained in 94% of all potentially studied patients. All data were compiled in a computerized databank and analyzed with the Number Cruncher Statistical System (Hintze, Kaysville, UT). Statistical analysis of categorical variables was performed on cross-tables using the Pearson 
2 test. Continuous variables were analyzed with the two-sample t test, if the variances of the groups were equal; otherwise, the Mann-Whitney U test was used. Survival curves were estimated following the method of Kaplan-Meier [7]. Differences of survival rates between the two treatment groups were analyzed by the log-rank test. For ischemic event-free survival analysis, events were defined as all late cardiac deaths, new myocardial infarctions, recurrent angina, and coronary reinterventions (bypass or PTCA). When patients had incomplete follow-up they were censored at the date of last follow-up. For analysis of the angina-free, reinfarction-free, coronary reintervention-free, and ischemic event-free survival, death due to all causes was considered as mortality. For analysis of predictors for different event-free survival estimates the Cox proportional hazards regression model [8] was used in patients with at least 6 months of follow-up. Regression analysis was performed with a selection from 22 preoperative and intraoperative variables, to which the procedure (LITA versus BITA) was added (Appendix), with backward elimination and was continued until all nonsignificant predictors were removed. In Table 5 the relative risks are calculated from the ß estimates, with 95% confidence limits using the standard errors of the ß estimates. In all statistical tests a two-sided p value less than 0.05 was considered to be significant.
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Results
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The preoperative characteristics of the patients that were available for follow-up (Table 1) showed no significant (NS) difference in sex, preoperative angina class, heart failure, infarction, hypertension, or diabetes between study groups. However, BITA patients were younger (mean age, 53.7 versus 56.0 years; p = 0.002) and smoked less (35.9% versus 51.5%; p = 0.001), but had more often hyperlipidemia (43.1% versus 33.3%; p = 0.027) than their control LITA patients. The extent of coronary artery disease and left ventricular function as expressed by left ventricular end-diastolic pressure were comparable for both study groups (Table 2). Coronary angiography showed three-vessel disease in about 60% of the patients in both study groups. At operation, the mean total number of constructed anastomoses was similar in both groups. Because of the study design, there were more anastomoses performed with vein grafts in the LITA group, whereas in BITA patients this was done more often with the ITAs (Table 3). In BITA patients the ITA were more often used to perform sequential grafting than in the LITA group. Consequently, in 35.7% of the BITA patients no vein grafts were used (complete arterial revascularization).
Overall survival
The mean duration of follow-up was comparable for both study groups (116.2 ± 32.0 months in the BITA versus 120.6 ± 28.3 months in the LITA group; p = NS) (Table 4). Also the range of the duration of follow-up (7 to 166 months for BITA versus 5 to 165 months for LITA patients) was comparable. A short follow-up in some patients was mainly caused by their early death. The total number of follow-up years was for BITA 2,256 and for LITA patients 2,501 years (p = NS). During follow-up 32 (12.9%) BITA and 40 (17.2%) LITA patients died (p = NS). Cause of death was noncardiac in the BITA and LITA group 59% and 55%, cardiac 28% and 35%, and unknown 13% and 10%, respectively (p = NS). The overall survival estimates during 13 years of follow-up were similar (Fig 1). At 13 years 76.2% ± 5.9% of the BITA and 78.3% ± 3.8% of the LITA patients were still alive (p = NS). Multivariate analysis of predictors for overall late mortality showed age as the only predictor (p < 0.0001) (Table 5).
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Fig 1. Overall survival estimates for the left internal thoracic artery (LITA) and bilateral internal thoracic arteries (BITA) patient groups. (NS = not significant.)
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Cardiac survival
If the causes of death that were cardiac or unknown were grouped together, a total of 13 (5.2%) of the BITA and 18 (7.7%) of the LITA patients died during follow-up (p = NS). The cardiac survival estimates during 13 years of follow-up were similar. At 13 years, in 91.1% ± 2.7% of the BITA and 91.0% ± 2.2% of the LITA patients, death due to a cardiac or unknown cause did not occur (p = NS).
Recurrent ischemia
The distribution into the different postoperative angina classes of the patients is shown in Table 4 and was similar in both study groups (p = NS). However, in the LITA group there were more patients with recurrent angina (68, 29.2%) than in the BITA group (51, 20.5%) (p = 0.0268). The number of patients using antianginal medication was similar, 71 (30.6%) of the LITA and 61 (24.7%) of the BITA patients (p = NS). The angina-free survival estimates of patients during 13 years of follow-up were better in BITA than in LITA patients (Fig 2). At 13 years 48.5% ± 9.8% of the BITA and 29.8% ± 6.9% of the LITA patients were still alive and angina-free (p < 0.001). Multivariate analysis of predictors for recurrent angina showed female gender (p = 0.0038) and nonuse of both ITAs (p = 0.0117) were such predictors. The use of BITAs (p = 0.0019) and age (p = 0.0008) were predictors for angina-free survival (Table 5).
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Fig 2. Angina-free survival estimates for the left internal thoracic artery (LITA) and bilateral internal thoracic arteries (BITA) patient groups.
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New myocardial infarction
A new myocardial infarction occurred more often in LITA (24, 10.4%) than in BITA (12, 4.9%) patients (p = 0.0220). The survival estimates of patients who were myocardial infarction-free during 13 years of follow-up were better in BITA than in LITA patients (Fig 3). At 13 years 72.3% ± 5.8% of the BITA and 63.8% ± 5.5% of the LITA patients were still alive and infarction-free (p < 0.01). Multivariate analysis showed that a low number of performed ITA anastomoses was a predictor for the occurrence of late myocardial infarction (p < 0.0001). Age was a predictor for myocardial infarction-free survival (p < 0.0001) (Table 5).
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Fig 3. Infarction-free survival estimates for the left internal thoracic artery (LITA) and bilateral internal thoracic arteries (BITA) patient groups.
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Coronary reinterventions
Coronary reinterventions, which are repeat coronary bypass grafting or PTCA with or without stenting, occurred in 27 (11.6%) LITA and 20 (8.0%) BITA patients (p = NS). The survival estimates of patients who were coronary reintervention-free during 13 years of follow-up were better in BITA than in LITA patients (Fig 4). At 13 years, 69.1% ± 6.2% of the BITA and 53.8% ± 9.4% of the LITA patients were still alive and coronary reintervention-free (p < 0.05). Multivariate analysis showed that age was a predictor for coronary reintervention-free survival (p < 0.0001) (Table 5).
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Fig 4. Reintervention-free survival estimates for the left internal thoracic artery (LITA) and bilateral internal thoracic arteries (BITA) patient groups.
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Ischemic event-free survival
Death, recurrent angina, new myocardial infarction, or coronary reinterventions occurred more frequently in LITA (49.4%) than BITA (33.3%) patients (p = 0.0004). At 13 years of follow-up, the ischemic event-free survival estimates were better for BITA patients (47.5% ± 8.4%) than for LITA patients (35.4% ± 5.1%) (p < 0.001) (Fig 5). Multivariate analysis showed that BITA was a predictor for ischemic event-free survival (p = 0.0005) (Table 5). The ischemic event-free survival at 13 years was not significantly different for 90 patients in whom the RITA was anastomosed to the right coronary artery versus 158 patients in whom the RITA was anastomosed to the circumflex artery (61.8% ± 6.5% and 56.5% ± 5.4%, respectively). Also, the ischemic event-free survival at 13 years for 89 patients, in whom a complete arterial revascularization with both ITAs was performed, was not significantly different from 159 patients in whom BITA with additional vein grafting was performed (56.9% ± 5.5% and 56.5% ± 5.4%, respectively).
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Fig 5. Ischemic-event-free survival estimates for the left internal thoracic artery (LITA) and bilateral internal thoracic arteries (BITA) patient groups.
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Comment
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In comparison with a previous study of our group [5], in which we were unable to demonstrate any significant difference in outcome between BITA and LITA grafting, this study demonstrates several significant differences in outcome. This might be attributed to the longer duration of follow-up (116 and 121 months, respectively) and a larger sample size. In a recent meta-analysis of major studies with substantial follow-up after BITA grafting, it was shown that only four of eight studies demonstrated a significantly better survival after BITA versus LITA grafting [9]. Lytle and coworkers [4] recently showed in a large study with 2,001 BITA and 8,123 LITA patients that survival for the BITA group was 94%, 84%, and 67%, and for the LITA group 92%, 79%, and 64% at 5, 10, and 15 postoperative years, respectively (p < 0.001). These differences in survival are, although statistically significant, still rather small. In the current study, we were again unable to demonstrate a significant difference in overall survival between both study groups after 13 years. As might have been still the case in our study, most studies that did not prove a significant difference in survival lack a mean follow-up of more than 10 years or have sample sizes that are too small, or both. Our multivariate analysis of predictors for overall late mortality showed age as the only significant predictor. One has to consider, however, that in both of our study groups the mean age of the patients was relatively low, and that there was a low incidence of potentially relevant patient-related factors, such as female gender, left main disease, poor left ventricular function, history of congestive heart failure, or diabetes. Lytle and colleagues [4] showed that single ITA grafting (versus BITA grafting) increased the risk for late death, but that patient-related factors, like female gender, younger age, chronic heart failure, peripheral vascular disease, smoking history, diabetes, left main coronary artery disease, higher grade of left ventricular dysfunction, or hypertension were more important predictors for late death. Recurrent angina is considered a "soft" end point as it is a subjective variable. On the other hand, angina is the most important disabling factor. In a recent metaanalysis of seven comparative studies, it was shown that in only three of these a better angina-free survival was demonstrated after BITA than after LITA grafting [9]. In our current study we demonstrated about 10% difference in the incidence of recurrent angina and about 20% difference in angina-free survival in favor of the BITA group. Our multivariate analysis demonstrated that the use of BITA has a protective effect against recurrent angina. Sergeant and coworkers [10] showed that more extensive arterial grafting reduced the early return of angina, but that the delay of late angina by use of arterial grafting is clinically trivial. However, in this study the mean follow-up was only 6.4 years and it is not clear how many BITA patients with sufficient follow-up were included. Although the definition of a myocardial infarction may vary between institutions, a recent meta-analysis of six studies that compared the incidence of this event after BITA or LITA grafting, showed in three such studies a significantly better myocardial infarction-free survival after BITA grafting [9]. In our current study we demonstrated a twofold prevalence of late infarction in the LITA patient group (10.4%) as compared with the BITA patient group (4.9%). Our multivariate analysis showed that a higher number of ITA anastomoses had a protective effect against late infarction. Other investigators have also demonstrated that single ITA grafting (versus BITA grafting) is one of the predictors for late infarction [11, 12]. Sergeant and coworkers [10, 13] found no additional benefit for the use of both ITA on the freedom of myocardial infarction. However, in only a minority of their patients the RITA was anastomosed to another vessel other than the diagonal branch of the left anterior descending artery and the mean number of grafts per patients was only 2.4. Coronary reintervention may relate to reoperation or PTCA. A common indication for reintervention is the progression of atherosclerotic disease in the native circulation or in saphenous vein grafts. A metaanalysis of seven comparative studies showed that in four of these, BITA grafting resulted in significantly less reinterventions than LITA grafting [9]. Although in the current study we could not demonstrate a significant difference in the incidence of reinterventions, BITA patients showed a significantly better reintervention-free survival. Lytle and associates [4] have shown that single ITA grafting, among other mainly patient-related variables, is a significant predictor for later reoperation as PTCA. Ischemic event-free survival is the most important study end point to evaluate outcome of coronary interventional therapies. Although different definitions are used, ischemic event-free survival should include all relevant cardiac-related events. Metaanalysis of six comparative studies showed that in only two of these a significantly better freedom from any ischemic event for patients receiving BITA grafts could be demonstrated [9]. Many of these studies lack sufficient follow-up or sample size, or both. In our current study, where we included recurrent angina as an ischemic event, we demonstrated a significantly better 13-year event-free survival for BITA (47.5%) than for LITA (35.4%) patients. Some investigators reported a better outcome after BITA grafting when both ITAs are anastomosed to left-sided coronary arteries [14]. However, Lytle and associates [4] demonstrated that neither total arterial revascularization nor the specific vessels grafted with BITA improved results (late death, reoperation, or PTCA) compared with the general strategy of BITA grafting. Our current study confirms these findings from the Cleveland Clinic. Our multivariate analysis showed that the use of both ITAs is a predictor for such an ischemic event-free survival. Lytle [4] and Buxton [12] and their colleagues excluded angina from their analyses. The latter group demonstrated the use of a single ITA (versus BITA grafting) was a predictor for all-cause mortality, late myocardial infarction, or late reoperation [12]. They also demonstrated that the use of BITA grafting is a relatively weak predictor of outcome compared with other patient-related predictors. Lytle and coworkers [4] found that death, reoperation, and PTCA were more prevalent in patients undergoing single rather than BITA grafting and that of all outcome variables that are positively influenced by BITA grafting, its effects have the least influence on survival. Other variables, mainly patient related, seem to have a larger impact on survival.
In summary, for the decision to use one or two ITAs, the positive influence of BITA grafting on ischemic event-free survival is more important than its effect on survival per se. Neither total arterial revascularization nor the specific vessels grafted with BITA is relevant in terms of ischemic event-free survival, compared to the general strategy of BITA grafting.
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Acknowledgments
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In this study patients are included who were operated by E. Berreklouw, MD, PhD, J.H. Bavinck, MD (deceased), J.J. Bredée, MD, PhD, P.N. Hendel, MD, Y.A.S. Mashhour, MD, FRCS, and J.P.A.M. Schönberger, MD, PhD.
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Appendix
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Variables considered as independent variables in the Cox proportional regression analysis
Patient-related variables |
| Demographic variables: |
| Sex |
| Age |
| Symptoms of reversible ischemia: |
| Angina class |
| Positive ECG-stress test |
| Positive thallium-stress test |
| Cardiac comorbidity: |
| Smoking |
| History of heart failure |
| Previous myocardial infarction |
| Hypertension |
| Hyperlipidemia |
| Diabetes |
| Coronary artery disease: |
| Left mainstem |
| LAD |
| RCX |
| RCA |
| Number of diseased coronary arteries |
| Left ventricular function: |
| Left ventricular end-diastolic pressure |
| Procedure-related factors |
| Kind of procedure |
| BITA |
| Surgeon |
| Number venous anastomoses |
| Number ITA anastomoses |
Complete revascularization
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BITA = left and right internal thoracic arteries with or without vein grafts; CX = circumflex coronary artery; ECG = electrocardiogram; LAD = left anterior descending artery; LITA = left internal thoracic artery with vein grafts; RCA = right coronary artery.
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Abstract
Introduction
