Off-Pump Bilateral Internal Thoracic Artery Grafting in Right Internal Thoracic Artery to Right Coronary System

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1 Off-Pump Bilateral Internal Thoracic Artery Grafting in Right Internal Thoracic Artery to Right Coronary System ADULT CARDIAC Hyun-Chel Joo, MD, Young-Nam Youn, MD, PhD, Gijong Yi, MD, PhD, Byung-Chul Chang, MD, PhD, and Kyung-Jong Yoo, MD, PhD Division of Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Yonsei University Health System, Seoul, Republic of Korea Background. Despite many large-volume studies on the use of bilateral internal thoracic artery (ITA) grafts, the benefits of a bilateral (B)ITA graft over a single (S)ITA graft for CABG remain controversial. This study compared midterm outcomes of BITA to SITA grafting in off-pump coronary artery bypass (OPCAB), focusing primarily on the right (R)ITA to right coronary artery (RCA) system. Methods. From January 2000 to December 2009, 1,749 patients underwent isolated OPCAB with ITA grafts. Using propensity score matching, 366 BITA patients could be pairwise propensity matched to a SITA patient. We compared midterm survival and major adverse cardiac and cerebrovascular event (MACCE) between the 2 groups. All patients in the BITA group underwent bilateral ITA grafting with the RITA anastomosed to the RCA system. Mean follow-up was months (range, 5 to 120 months). Results. Overall survival at 10 years was not significantly different between the 2 groups (84.6% vs 84.1%; p 0.955). The 10-year cardiac-related death-free rate also did not significantly differ between the groups (90.0% vs 90.9%; p 0.871). The 10-year MACCE-free rate did not significantly differ between the 2 groups (79.7% vs 74.6%; p 0.303). Conclusions. At 10-year follow-up, BITA grafting did not offer advantages over SITA grafting in midterm outcomes, at least in the RITA to RCA system. The BITA grafting was similar to SITA grafting in overall and cardiac survival, and MACCE rates. (Ann Thorac Surg 2012;94:717 25) 2012 by The Society of Thoracic Surgeons The choice of conduit for coronary artery bypass grafting has always been an important issue to cardiac surgeons who perform coronary artery bypass graft (CABG) surgery [1]. The use of the left internal thoracic artery (LITA) graft became the gold standard since the Cleveland Clinic group reported that internal thoracic artery (ITA) to left anterior descending (LAD) was better than vein graft in prolonging survival and preventing ischemic events [2]. The excellent outcomes associated with ITA graft led several groups to pursue the use of bilateral ITA as the preferred approach [2, 3]. Since then, numerous retrospective studies have reported that bilateral ITA (BITA) grafting has a clear advantage over single ITA (SITA) grafting in long-term survival, cardiac mortality, and cardiac events [4 9]. However, BITA grafting is actually only used in a small proportion of CABG patients (4% in the US and approximately 10% in Europe) [10, 11], and several studies [12 15] could not find a significant benefit of BITA grafting over SITA grafting. Therefore, the benefits of BITA grafting over SITA grafting for CABG Accepted for publication April 16, Address correspondence to Dr Yoo, Division of Cardiovascular Surgery, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Yonsei University Health System, 250 Seongsanno, Seodaemun-gu, Seoul , Republic of Korea; kjy@yuhs.ac. remain controversial. The goal of this study was to compare the 10-year outcomes of BITA grafting to SITA grafting in off-pump coronary artery bypass (OPCAB), mainly focusing on the right ITA (RITA) to right coronary artery (RCA) system strategy. Patients and Methods Patients From January 2000 to December 2009, 1,812 patients underwent isolated OPCAB at the Yonsei Cardiovascular Hospital of Yonsei University Health System in Seoul, Korea. After exclusion of patients who underwent OPCAB without internal thoracic artery grafts, 1,749 patients (96.5%) who received ITA grafts were entered into the study. Among these patients, 1,357 (77.6%) underwent OPCAB with SITA grafts (SITA group), and 392 (22.4%) underwent OPCAB with BITA grafts by using RITA to RCA system strategy (BITA group). The baseline characteristics of the 2 groups were different in that the BITA patients were younger and had a higher incidence of multivessel disease and a lower incidence of chronic renal failure. To balance the distribution of baseline risk factors between the SITA and BITA patients, a propensity-score matching technique was used. Propensity scores were created to quantity the probability of receiv by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc

2 ADULT CARDIAC 718 JOO ET AL Ann Thorac Surg OFF-PUMP BITA GRAFTING 2012;94: ing BITA grafting. Propensity scores were obtained by using a multivariate logistic regression model based on the following 10 preoperative baseline characteristics with a significance level of less than 0.2 in univariate analyses: age, female sex, diabetes mellitus, peripheral occlusive disease, prior percutaneous transluminal coronary angioplasty, chronic renal failure, recent myocardial infarction, 3-vessel disease, left ventricular ejection fraction (LVEF), and low LVEF ( 0.35). The c statistic for the propensity model was 0.83 (95% confidence interval, 0.75 to 0.91: p 0.01). This mode was well calibrated (Hosmer- Lemeshow goodness of fit 2 was 8.15; p 0.42). The SITA and BITA patients were then matched to each other using a 1:1 ratio on the value of a propensity score. By using propensity score matching, 366 (93.3%) BITA patients could be pairwise propensity matched to 366 (26.9%) SITA patients. Grafting Strategy The decision whether to use SITA or BITA grafting was not random but was decided according to surgeon s preference, patients underlying condition, stenosis and size of target vessel, and status of the ascending aorta. The BITA grafting was used in relatively young patients with small size and severe stenosis of target vessel. When size discrepancy between RITA and target vessel was less than 50%, or stenosis of target vessel was more than 80%, the use of BITA was considered. Also when there was a visible or palpable atheroma in the ascending aorta on intraoperative transesophageal echocardiography, the use of BITA was considered to avoid touching the ascending aorta. In the SITA group, the LITA was used in all patients. The LITA was mainly anastomosed to the LAD artery. For other coronary arteries, the radial artery as a composite graft or a free graft of saphenous vein was used. In the BITA group, the LITA and radial artery as composite grafts were used for left coronary anastomosis; the RITA only was used for right coronary anastomosis. The RITA was mainly used as an in situ graft for the RCA system. If the length of the RITA was not sufficient in cases of posterior descending or posterolateral branch anastomosis, the distal portion of the RITA was extended using a radial artery segment or saphenous vein. Operative Technique The operation was performed under general endotracheal anesthesia with continuous Swan-Ganz catheter monitoring, transesophageal echocardiography, and arterial pressure monitoring. All operations were performed under the off-pump method through a full sternotomy incision. The left internal thoracic artery was used in all patients, and the RITA, radial artery, and saphenous vein were used if necessary. The ITA was harvested in a semi-skeletonized method, using very low voltage unipolar electrocautery. The radial artery was harvested from the nondominant forearm in a pedicled fashion, using a Harmonic scalpel (Ethicon Endosurgery, Cincinnati, OH). Heparin with papaverine was used to avoid vasospasm of the ITA, and a calcium channel blocker (diltiazem) was used to prevent spasm of the radial artery during the operation. Heparin was given at a dose of 100 U/kg to achieve a target activated clotting time of at least 300 seconds during the operation. For cardiac stabilization and displacement, we used an Octopus tissue stabilizer and Starfish Heart Positioner (Medtronic, Minneapolis, MN) during construction of the anastomosis. Intracoronary shunt was mainly used for the LAD anastomosis and the proximal snaring technique using a silicone elastomer was used for anastomosis of other left coronary artery system vessels. For right coronary anastomosis, an intracoronary shunt was usually used for the main RCA and the proximal snaring technique was used for the posterior descending or posterolateral artery. To remove blood from the sites of arteriotomy, a mixed carbon dioxide blower and irrigation with warm saline were used. Before the sternum was closed, the ITA graft was wrapped in thymic tissue to prevent injury at reoperation. Data Collection Preoperative and perioperative data were collected prospectively from the cardiac research databases at our institution. Follow-up data were obtained from reviewing hospital charts, conducting telephone interviews, and searching the National Death Index. The collection of long-term outcome was complete in 98.1% of patients. A 97.8% follow-up was achieved in the SITA group, with 8 patients lost to follow-up. In the BITA groups, a 98.4% follow-up was achieved, with 6 patients lost to follow-up. The mean follow-up duration was months (range, 5 to 120 months). A total of 5,952 patient-years of follow-up data were available for analysis. Our study was conducted after approval by the Institutional Review Board of Yonsei University College of Medicine (Yonsei Institutional Review Board No ). The individual patient consent was waived. Long-Term Outcome Assessment Midterm outcomes were assessed by all-cause mortality, cardiac-related mortality, reintervention, and major adverse cardiac and cerebrovascular event (MACCE). The MACCE were defined as death from any cause, nonfatal myocardial infarction, reintervention, or stroke. Myocardial infarction was defined as occurrence of wall motion abnormality or MB fraction of creatine kinase elevation with appearance of new Q waves or ST segment elevation of more than 2 mm on electrocardiogram. Reintervention was defined as the percutaneous coronary intervention (PCI) after surgery or redo coronary bypass surgery. Statistical Analyses Statistical analyses were performed with SPSS for Windows, release 18.0 (SPSS Inc, Chicago, IL). The null hypothesis of this study was that there are no differenced in midterm outcomes between BITA patients and SITA patients in the right internal thoracic artery to right coronary system. Previous studies have shown that rates of cardiac event were 14% in SITA and 7% in BITA at 10-year follow-up [8 18]. We estimated a sample size of

3 Ann Thorac Surg JOO ET AL 2012;94: OFF-PUMP BITA GRAFTING Table 1. Baseline Patient Characteristics of Unmatched Groups and Propensity-Matched Groups Variables SITA Group (n 1,357) Unmatched Groups BITA Group (n 392) p Value SITA Group Propensity-Matched Groups 719 BITA Group p Value ADULT CARDIAC Age (years) Female, n (%) 505 (37.2%) 156 (39.8%) (21.3%) 87 (23.8%) Hypertension, n (%) 810 (59.7%) 225 (57.4%) (53.3%) 192 (52.5%) Diabetes mellitus, n (%) 554 (40.8%) 150 (38.3%) (39.3%) 138 (37.8%) Smoker, n (%) 551 (50.6%) 160 (41.8%) (56.6%) 198 (54.1%) PAOD, n (%) 210 (15.5%) 69 (17.6%) (17.2%) 63 (17.2%) 0.99 Old CVA, n (%) 135 (9.9%) 33 (8.4%) (8.2%) 27 (7.4%) Prior PTCA, n (%) 202 (14.8%) 47 (12.0%) (9.9%) 39 (10.7%) COPD, n (%) 91 (6.7%) 29 (7.4%) (4.4%) 19 (5.2%) Chronic renal failure, n (%) 118 (8.7%) 21 (5.4%) (6.6%) 12 (3.3%) Acute coronary syndrome, n (%) 1,074 (79.1%) 306 (78.1%) (74.6%) 267 (73.0%) Recent MI ( 21 days), n (%) 419 (30.9%) 129 (32.9%) (31.1%) 119 (32.5%) vessel disease, n (%) 1,295 (95.4%) 383 (97.7%) (96.2%) 355 (97.0%) Left main disease, n (%) 350 (25.8%) 106 (27.0%) (19.7%) 78 (21.3%) LVEF Low LVEF ( 0.35) n (%) 142 (0.105) 45 (0.115) (0.082) 31 (0.085) NYHA class, n (%) I 421 (31.0%) 123 (31.4%) (31.1%) 118 (32.2%) II 651 (48.0%) 192 (49.0%) (49.7%) 174 (47.5%) III 221 (16.3%) 62 (15.8%) (15.8%) 55 (15.0%) IV 59 (4.3%) 14 (3.6%) (3.3%) 19 (5.2%) BITA bilateral internal thoracic artery; COPD chronic obstructive pulmonary disease; CVA cerebrovascular accident; LVEF left ventricular ejection fraction; MI myocardial infarction; NYHA New York Heart Association; PAOD peripheral artery occlusive disease; PTCA percutaneous transluminal coronary angioplasty; SITA single internal thoracic artery. 366 patients would provide 0.87 power on the use of a 2-tailed value of p All data are expressed as mean standard deviation (SD) or frequency and percentage. For comparison of characteristics between the unmatched groups, continuous variables were compared using the t test and categoric variables were compared using the 2 or Fisher exact test. In comparisons between the matched groups, means were compared using a paired Student t test and frequencies were analyzed using the McNemar test. Postoperative outcome and MACCE were also compared using these same paired tests. The Cox proportional hazard regression model was used to identify predictors of overall death, cardiac death, and MACCE. Long-term survival and MACCE curves were estimated by the Kaplan-Meier method. Differences between curves were compared using the log-rank test. In all statistical tests, statistical significance was defined as a 2-tailed p value less than Results Patient Characteristics After propensity score matching, the demographics of the 2 groups (366 patients each) were similar with respect to age, gender, smoking status, incidence of acute coronary syndrome, multivessel disease, left main disease, previous percutaneous transluminal coronary angioplasty, and left ventricular ejection fraction (LVEF). The groups were also well matched for comorbidities including hypertension, diabetes, old cerebrovascular accident, chronic renal failure, and peripheral occlusive disease. The baseline characteristics of the SITA and BITA groups are shown in Table 1. Operative Data The mean number of distal anastomosis was in the SITA group and in the BITA group, and these values were not significantly different (p 0.071). Percentages of complete revascularization, composite Y graft, and sequential graft were not different between the 2 groups. However, the mean number of vein grafts was significantly different; in the SITA group and in the BITA group (p 0.001). Total arterial revascularization was performed in significantly more patients in the SITA group (335, 91.5%) than in the BITA group (291, 79.5%; p 0.001; Table 2). Early Operative Results The hospital mortality was 0.8% in the SITA group and 0.5% in the BITA group (p 0.99). The morbidities, including perioperative myocardial infarction, low cardiac output syndrome, reoperation for bleeding, renal support therapy, and pulmonary complication were similar between the 2 groups. Incidence of sternal wound reconstruction was 0.8% in the SITA group and 2.2% in the BITA group. The BITA group had higher incidence of

4 ADULT CARDIAC 720 JOO ET AL Ann Thorac Surg OFF-PUMP BITA GRAFTING 2012;94: Table 2. Operative Data Variable Distal anastomosis, mean SD Complete revascularization, n (%) Use of vein graft, mean SD Total arterial grafting, n (%) Composite Y graft, n (%) Sequential graft, n (%) SITA Group BITA bilateral internal thoracic artery; thoracic artery. BITA Group p Value (92.2%) 346 (94.5%) (79.5%) 335 (91.5%) (86.9%) 306 (83.6%) (34.4%) 118 (32.2%) SITA single internal sternal wound reconstruction, which did not reach significant difference (p 0.227). The mean duration of operation was minutes and minutes in the SITA and BITA groups, respectively (p 0.001). The mean length of ventilation time, intensive care unit stay, and hospital stay were not significantly different between the 2 groups. The detailed descriptions of early operative result are summarized in Table 3. Cardiac Survival During the follow-up period, 156 deaths occurred, 96 of which were cardiac related. The cardiac-related mortality was not significantly different between the SITA (76, 5.6%) and the BITA (20, 5.1%) groups. The cardiac-related death-free survival rate at 10 years was not significantly different; 91.6% 1.1% in the SITA group and 93.4% 1.7% in the BITA group (p 0.471, Appendix Fig 1B). Similar results were also observed between the propensity-matched groups. The cardiac-related death-free survival rate at 10 years was not significantly different; 90.0% 1.7% in the SITA group and 90.9% 1.7% in the BITA group between the propensity-matched groups (p 0.871, Fig 1B). Reintervention Rate During the follow-up period, a total of 107 PCIs were performed in 84 patients, with 72 patients requiring 1 intervention, 12 patients requiring 2 interventions, and 3 patients requiring 3 interventions. A total of 63 (4.7%) patients in the SITA group and 21 (5.4%) patients in the BITA group underwent PCI. Only 1 patient underwent redo-cabg in the BITA group (Table 4). The reintervention-free rate at 10 years was 89.6% 1.7% in the SITA group and 90.6% 2.6% in the BITA group, and these rates also were not significantly different (p 0.674, Appendix Fig 1C). Similar results were also observed between the propensity-matched groups. The reintervention-free rate at 10 years was 88.1% 2.4% in the SITA group and 84.0% 4.6% in the BITA group, and these rates also were not significantly different between the propensity-matched groups (p 0.186, Fig 2A). MACCE The overall MACCE, including deaths, myocardial infarction, PCI, and redo CABG occurred in 234 (13.3%) patients. The MACCE-free rate at 10 years was 76.2% 2.1% in the SITA group and 80.6% 3.2% in the BITA group, and these rates showed no significant difference Overall Survival The mean follow-up duration was months (range, 5 to 120 months) and was not significantly different between the 2groups ( months in the SITA vs months in the BITA group; p 0.251). The range of follow-up duration was also not significantly different between the 2 groups (5 to 120 months for the SITA group vs 6 to 118 months for the BITA group). During the follow-up period, 126 (9.3%) patients in the SITA group and 33 patients (8.4%) in the BITA group died. The overall survival rate at 10 years was % in the SITA group and % in the BITA group, which was not significantly different between the 2 groups (P 0.314; Appendix Fig 1A). Similar results were also observed between the propensitymatched groups. The overall survival rate at 10 years was 84.6% 2.6% in the SITA group and 84.1% 3.5% in the BITA group, which was not significantly different between the propensity-matched groups (p 0.955; Fig 1A). Table 3. Operative Results Between SITA and BITA Groups Variable SITA Group BITA Group P Value Mortality 3 (0.8%) 2 (0.5%) 0.99 Stroke 4 (1.1%) 3 (0.8%) 0.99 Perioperative MI 2 (0.5%) 2 (0.5%) 0.99 Low cardiac output 11 (3.0%) 12 (3.3%) 0.99 syndrome Reoperation for 2 (0.5%) 3 (0.8%) 0.99 bleeding Renal support 16 (4.4%) 19 (5.2%) therapy Pulmonary 17 (4.6%) 24 (6.6%) complication Sternal wound 3 (0.8%) 8 (2.2%) reconstruction Mean duration of operation (minutes) Mean duration of ventilation (hours) Mean length of ICU stay (hours) Mean length of hospital stay (days) BITA bilateral internal thoracic artery; ICU intensive care unit; MI myocardial infarction; SITA single internal thoracic artery.

5 Ann Thorac Surg JOO ET AL 2012;94: OFF-PUMP BITA GRAFTING 721 Fig 1. Kaplan-Meier curves comparing the single internal thoracic artery (SITA; ) group and those of the bilateral internal thoracic artery (BITA; ---)group in (A) overall survival and (B) cardiacrelated death-free survival in matched groups. ADULT CARDIAC between the 2 groups (p 0.608, Appendix Fig 1D). Similar results were also observed between the propensity-matched groups. The MACCE-free rate at 10 years was 79.7% 2.2% in the SITA group and 74.6% 3.3% in the BITA group, and these rates showed no significant difference between the propensity-matched groups (p 0.303, Fig 2B). Cox regression analysis demonstrated that the independent predictors of MACCE were chronic renal failure (hazard ratio, 3.32:95% confidence interval, 1.50 to 5.01: p 0.01) and low LVEF (hazard ratio, 2.44:95% confidence interval, 1.05 to 5.76: p 0.02). The BITA grafting was not found to be a significant predictor of MACCE (Table 5). Comment Our study demonstrated that BITA grafting, including the RITA to RCA system, did not have an advantage over SITA grafting in midterm survival. Similar to overall and cardiac survival, myocardial infarction, reintervention, cerebrovascular events, and MACCE were similar between the 2 groups. There has been much debate over the benefit of BITA grafting over SITA grafting, and during the past decade many retrospective studies have reported a clear advantage of BITA grafting over SITA grafting [4 9]. Lytle and Table 4. Major Adverse Cardiac and Cerebrovascular Events Rates Between SITA and BITA Groups Variable SITA Group BITA Group p Value Cumulative MACCE 71 (19.4%) 72 (19.7%) 0.99 Death 43 (11.7%) 38 (10.4%) Myocardial infarction 11 (3.0%) 12 (3.3%) 0.99 PCI 30 (8.2%) 31 (8.5%) 0.99 Redo CABG 0 (0%) 1 (0.3%) 0.99 Cerebrovascular events 8 (2.2%) 9 (2.5%) 0.99 BITA bilateral internal thoracic artery; CABG coronary artery bypass grafting; MACCE major adverse cardiac and cerebrovascular events; PCI percutaneous coronary artery intervention; SITA single internal thoracic artery. colleagues [5, 7] reported that use of BITA over SITA had benefits of improved survival and fewer cardiac events after 5, 10, 15, and 20 years. In another study by Stevens and colleagues [6] BITA grafting over SITA grafting had benefits in overall and cardiac survival, and cardiac events on 10-year follow-up. On the other hand, some groups did not find any advantage in survival but reported benefits on repeat revascularization with BITA grafting. Pick and colleagues [16] did not demonstrate any difference in overall survival but reported that the BITA group had a lower incidence of cardiac death, acute myocardial infarction, and angina recurrence. Berreklouw and colleagues [9] and Endo and colleagues [17] also reported that BITA had no benefit in overall and cardiac-related mortality, but had significant benefit in angina return, acute myocardial infarction, and global ischemic events. Previous observational studies seem to conclude that BITA grafting had a benefit over SITA grafting in long-term survival or at least in rates of reintervention. However, several groups demonstrated that BITA grafting had no advantage over SITA grafting. In the article by Naunheim and colleagues [14] there was no difference in 15-year survival in a matched series of single versus multiple IMA patients. In other casematched studies by Galbut and colleagues [12] and Dewar and colleagues [13] there were no benefits to multiple IMA grafting. Recently Taggart and colleagues [15] demonstrated similar clinical outcome for SITA and BITA at 1 year from the Arterial Revascularisation Trial (ART). Results from 10-year follow-up from this trial will provide more definitive evidence of benefit of BITA grafting. Benefits of BITA grafting over SITA graft for CABG thus remain controversial. Despite many large studies on the use of BITA grafts, one key factor associated with the use of BITA make comparison difficult. The key factor is that the strategy of BITA grafting is very different at each institution. The LITA to LAD has been used as an ideal bypass graft strategy in almost all institutions, whereas RITA is used to graft either the circumflex or RCA system. Diversity in the RITA grafting method can lead to different results for BITA grafting. The identification of the target anastomosis site of the

6 ADULT CARDIAC 722 JOO ET AL Ann Thorac Surg OFF-PUMP BITA GRAFTING 2012;94: Fig 2. Kaplan-Meier curves comparing the single internal thoracic artery (SITA; ) group and the bilateral internal thoracic artery (BITA; ---) group in (A) reintervention-free rate (B) major adverse cardiac and cerebrovascular eventfree survival rate in matched groups. (MACCE major adverse cardiac and cerebrovascular event.) RITA graft is important in analyzing the benefit of BITA over SITA. The LITA is routinely used to bypass the LAD at almost all institutions, but revascularization strategies of RITA are not equal among different institutions. The RITA may be used to graft either to the RCA system or circumflex artery; moreover, the RITA may be used as an in situ graft or a free graft. Some groups reported the results of anastomosis of the RITA to the left coronary system [13, 16, 19] whereas other groups reported the results of anastomosis of the RITA to RCA system [12]. These differences in strategy of RITA grafting may be a possible explanation for different observations for benefits of BITA over SITA. Schmidt and colleagues [20] reported that both ITAs had better long-term survival when used to bypass the left-side coronary system. According to their observation, survival at 9 years was 93% when the RITA was grafted to the circumflex artery, but only 70% when the RITA was grafted to the RCA system. In another similar study by Galbut and colleagues [12], who reported the results of anastomosis of the second ITA to the RCA system, they did not find any advantage of BITA grafting over SITA grafting on survival. They reported that the patency rate of the RITA was lower than that of the LITA (84.9% vs 92.1%, respectively). Similarly, Naunheim and colleagues [14] reported the results of BITA grafting using the second ITA to graft the RCA system; they did not find any survival benefit of BITA grafting over SITA grafting. These studies demonstrate that BITA grafting may have no advantage over SITA grafting when the second ITA bypass is to the RCA system. The results of our present study strongly support these data. In our study, the RITA was used for the RCA system Table 5. Multivariate Cox Proportional Hazard Regression Analyses of Major Adverse Cardiac and Cerebrovascular Events Univariate Analysis Multivariate Analysis Variable HR (95% CI) p Value HR (95% CI) p Value Age 2.25 ( ) 0.04 Female 1.41 ( ) 0.39 Hypertension 1.27 ( ) 0.51 Diabetes mellitus 2.99 ( ) 0.03 Smoker 1.34 ( ) 0.27 PAOD 1.49 ( ) 0.07 Old CVA 1.67 ( ) 0.22 Prior PTCA 1.11 ( ) 0.45 COPD 1.55 ( ) 0.56 Chronic renal failure 3.01 ( ) ( ) 0.01 Acute coronary syndrome 0.81 ( ) 0.54 Recent MI ( 21days) 1.31 ( ) vessel disease 0.92 ( ) 0.69 Left main disease 0.70 ( ) 0.28 LVEF 2.23 ( ) 0.15 Low LVEF ( 0.35) 2.01 ( ) ( ) 0.02 NYHA class III 2.45 ( ) 0.05 BITA grafting 0.81 ( ) 0.30 BITA bilateral internal thoracic artery; CI confidence interval; COPD chronic obstructive pulmonary disease; CVA cerebrovascular accident; HR hazard ratio; LVEF left ventricular ejection fraction; MI myocardial infarction; NYHA New York Heart Association; PAOD peripheral artery occlusive disease; PTCA percutaneous transluminal coronary angioplasty.

7 Ann Thorac Surg JOO ET AL 2012;94: OFF-PUMP BITA GRAFTING in all cases of BITA grafting. We did not find any advantage of BITA grafting over SITA grafting on survival or MACCE. Many reports have pointed out that patency of the RITA is not as good as that of the LITA when it is anastomosed to the RCA system. Because the RCA has a relatively large size compared with the left coronary system, size mismatch between RITA and RCA can have a tendency for competition flow, which can lead to worse patency. Sabik and colleagues [21] reported that decreasing stenosis in the proximal coronary artery is related to reduced ITA patency, especially when ITA is anastomosed to RCA compared with LAD. Recently, the last study from our institution [22] also demonstrated that RITA showed worse graft patency compared with free aortasaphenous graft in the overall population, and a significant difference was made in the moderate stenosis group. These studies emphasized that use of free aorta-saphenous grafts might be better than that of RITA in case of a moderate lesion of the RCA system in midterm follow-up. It is considered that the RITA may not have the advantage of arterial conduits when it is anastomosed to the RCA system. At this point, BITA grafting using the RITA to RCA system may not be as good as it has been thought to be. Additionally, we should pay attention to the fact that the percentage of total arterial grafting can affect observations for benefits of BITA over SITA. Although not definitely proven, many reports have demonstrated that total arterial grafting offered improved benefits in the long term compared with grafting using LITA and saphenous veins [23 26]. Because the BITA group has a usually higher percentage of total arterial grafting than the SITA group, the benefit of BITA over SITA can be a confounding result from the benefit of total arterial grafting. As a matter of fact, many reports showed data that have a large discrepancy in the percentage of total arterial grafting between the 2 groups or did not identify the percentage of total arterial grafting. In the study by Endo and colleagues [17] total arterial grafting was performed in 0% of the SITA group and 35.7% of the BITA group. In another study by Berreklouw and colleagues [9] total arterial grafting was performed in 59% of the SITA group and 90.2% of the BITA group. In large volume studies from the Cleveland clinic [3, 5], contents about the percentage of total arterial grafting were not included. In the present study, total arterial grafting was performed in 79.5% of the SITA group and 91.5% of the BITA group. These data show a smaller discrepancy of the percentage of total arterial grafting between the 2 groups than those of other studies. The current study could minimize the affect of total arterial grafting for assessing the benefits of BITA over SITA and could not find any advantage of BITA grafting over SITA grafting. At this point, there is a possibility that if the total arterial grafting is performed in the SITA group as in the BITA group, midterm outcome of the 2 groups may be similar. In this current study we did not observe any advantage of BITA grafting over SITA grafting. However, our results cannot prove that BITA grafting is actually not better than SITA grafting. It is possible that the RITA to RCA system may have a role in the outcome of BITA grafting. The BITA grafting may have better long-term outcomes over SITA grafting if the second ITA graft is connected to the left coronary system. Studies with longer follow-up may change these results. However, this study at least leads to the conclusion that BITA grafting using the RITA to RCA system is not better than SITA grafting with respect to 10-year survival and MACCE. Limitations This study is limited by its retrospective nature. Therefore, selection bias or unidentified confounding bias may influence the results. The data were obtained from 4 surgeons, so bias associated with surgeons may play an important role in our findings. However, they were all well-experienced surgeons who mainly performed offpump CABG and had nearly the same indication and strategy for bilateral grafting, which minimized bias associated with the surgeon. Another possible limitation is that our study did not consider the bias related to native coronary artery disease, such as degree of calcification, degree of stenosis, or length of lesion. Finally, the single-center experience may limit generalization. Conclusions In conclusion, BITA grafting did not have an advantage over SITA grafting in the midterm outcomes assessed, at least with the RITA to RCA system. The BITA grafting was similar to SITA grafting in terms of overall and cardiac survival, myocardial infarction, reintervention, cerebrovascular events, and MACCE. However, longer follow-up is needed to confirm these results. References Buxton BF, Hayward PA, Newcomb AE, Moten S, Seevanayagam S, Gordon I. Choice of conduits for coronary artery bypass grafting: craft or science? Eur J Cardiothorac Surg 2009;35: Loop FD, Lytle BW, Cosgrove DM, et al. Influence of the internal mammary artery graft on 10-year survival and other cardiac events. N Engl J Med 1986;314: Cameron A, Davis KB, Green G, Schaff HV. Coronary bypass surgery with internal-thoracic-artery grafts: effects on survival over a 15-year period. N Engl J Med 1996;334: Buxton BF, Komed M, Fuller JA, et al. Bilateral internal thoracic grafting may improve outcome of coronary artery surgery. Risk adjusted survival. Circulation 1998;98(suppl 19):II Lytle BW, Blackstone EH, Loop FD, et al. Two internal thoracic artery grafts are better than one. J Thorac Cardiovasc Surg 1999;117: Stevens LM, Carrier M, Perrault LP, et al. Single versus bilateral internal thoracic artery grafts with concomitant saphenous vein grafts for multivessel coronary artery bypass grafting: effects on mortality and event-free survival. J Thorac Cardiovasc Surg 2004;127: Lytle BW, Blackstone EH, Sabik JF, Houghtaling P, Loop FD, Cosgrove DM. The effect of bilateral internal thoracic artery grafting on survival during 20 postoperative years. Ann Thorac Surg 2004;78: Califiore AM, Di Giammarco G, Teodori G, et al. Late results of first myocardial revascularization in multiple vessel disease: single versus bilateral internal mammary artery with or without saphenous vein grafts. Eur J Thorac Surg 2004;26: ADULT CARDIAC

8 ADULT CARDIAC 724 JOO ET AL Ann Thorac Surg OFF-PUMP BITA GRAFTING 2012;94: Berreklouw E, Rademakers PP, Koster JM, van Leur L, van der Wielen BJ, Westers P. Better ischemic event-free survival after two internal thoracic artery grafts: 13 years of followup. Ann Thorac Surg 2001;72: Bridgewater B, Keogh B, Robin Kinsman R, Walton PKH; on behalf of the Society for Cardiothoracic Surgery in Great Britain and Ireland. Sixth National Adult Cardiac Surgical Database Report 2008: Demonstrating Quality. Henley-on- Thames, Oxfordshire, UK: Dendrite Clinical Systems Ltd; Tabata M, Grab JD, Khalpey Z, et al. Prevalence and variability of internal mammary artery graft use in contemporary multivessel coronary artery bypass graft surgery: analysis of the Society of Thoracic Surgeons National Cardiac Database. Circulation 2009;120: Galbut DL, Traad EA, Dorman MJ, et al. Twelve-year experience with bilateral internal mammary artery grafts. Ann Thorac Surg 1985;40: Dewar LR, Jamieson WR, Janusz MT, et al. Unilateral versus bilateral internal mammary revascularization. Survival and event-free performance. Circulation 1995;92(suppl 9):II Naunheim KS, Barner HB, Fiore AC. 1990: Results of internal thoracic artery grafting over 15 years: single versus double grafts update. Ann Thorac Surg 1992;53: Taggart DP, Altman DG, Gray AM, et al. Randomized trial to compare bilateral vs. single internal mammary coronary artery bypass grafting: 1-year results of the Arterial Revascularisation Trial (ART). Eur Heart J 2010;31: Pick AW, Orszulak TA, Anderson BJ, Schaff HV. Single versus bilateral internal mammary artery grafts: 10-year outcome analysis. Ann Thorac Surg 1997;64: Endo M, Nishida H, Tomizawa Y, Kasanuki H. Benefit of bilateral over single internal mammary artery grafts for Appendix multiple coronary artery bypass grafting. Circulation 2001;104: Taggart DP, D Amico R, Altman DG. Effect of arterial revascularization on survival: a systematic review of studies comparing bilateral and single internal mammary arteries. Lancet 2001;358: Fiore AC, Naunheim KS, Dean P, et al. Results of internal thoracic artery grafting over 15 years: single versus double grafts. Ann Thorac Surg 1990;49: Schmidt SE, Jones JW, Thornby JI, Miller CC III, Beall AC Jr. Improved survival with multiple left-sided bilateral internal thoracic artery grafts. Ann Thorac Surg 1997;64: Sabik JF, Lytle BW, Blackstone EH, Houghtaling PL, Cosgrove DM. Comparison of saphenous vein and internal thoracic artery graft patency by coronary system. Ann Thorac Surg 2005;79: Yi G, Youn YN, Song SW, Yoo KJ. Off-pump right coronary artery bypass with saphaneous vein or in-situ right internal thoracic artery. Ann Thoracic Surg 2010;89: Muneretto C, Negri A, Manfredi J, et al. Safety and usefulness of composite grafts for total arterial myocardial revascularization: a prospective randomized evaluation. J Thorac Cardiovasc Surg 2003;125: Guru V, Fremes SE, Tu JV. How many arterial grafts are enough? A population based study of midterm outcomes. J Thorac Cardiovasc Surg 2006;131: Junjiro Kobayashi. Radial artery as a graft for coronary artery bypass grafting. Circ J 2009;73: Tanaka H, Narisawa T, Mori T, Masuda M, Kishi D. Does myocardial revascularization with multiple arterial grafts improve the prognosis of dialysis patients? Circ J 2003;67: Appendix Fig 1. Kaplan-Meier curves comparing the single internal thoracic artery (SITA) group and those of the bilateral internal thoracic artery (BITA) group in the following: (A) overall survival; (B) cardiac-related death-free survival; (C) reintervention-free rate; and (D) major adverse cardiac and cerebrovascular event-free rate in unmatched groups.

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