Coronary Surgery in Patients With Peripheral Vascular Disease: Effect of Avoiding Cardiopulmonary Bypass

Coronary Surgery in Patients With Peripheral Vascular Disease: Effect of Avoiding Cardiopulmonary Bypass Shishir Karthik, FRCS, Ghassan Musleh, FRCS, Antony D. Grayson, BS, Daniel J. M. Keenan, FRCS, D. Mark Pullan, FRCS(C-Th), Walid C. Dihmis, FRCS(C-Th), Ragheb Hasan, FRCS(C-Th), and Brian M. Fabri, FRCS(Ed) Departments of Cardiothoracic Surgery and Research and Development, The Cardiothoracic Centre, Liverpool, and Department of Cardiothoracic Surgery, Manchester Royal Infirmary, Manchester, United Kingdom Background. An increasing number of patients with peripheral vascular disease are undergoing coronary artery bypass grafting. Such patients have an increased risk of adverse outcomes. Our aim was to quantify the effect of avoiding cardiopulmonary bypass in this group of patients. Methods. Between April 1997 and March 2002, 3,771 consecutive patients underwent coronary artery bypass grafting performed by five surgeons. Four hundred and twenty-two (11.2%) had peripheral vascular disease and of these, 211 (50%) received off-pump surgery. We used multivariate logistic regression analysis to assess the effect of off-pump surgery on in-hospital mortality and morbidity, while adjusting for treatment selection bias. Treatment selection bias was controlled for by constructing a propensity score, which was the probability of receiving off-pump surgery and included core patient characteristics. The C statistic for this model was 0.8. Results. patients were more likely to have preoperative renal dysfunction, previous gastrointestinal surgery, and less extensive disease. The left internal mammary artery was used more in off-pump compared to on-pump cases (90.1% vs 82.9%; p 0.033). In the univariate analyses, off-pump patients were less likely to have a postoperative stroke (p 0.007), and had shorter postoperative hospital stays (p < 0.001). However, the incidence of new atrial arrhythmia was higher (p 0.028). After adjustment for differences in case-mix (propensity score), avoidance of cardiopulmonary bypass was still associated with a significant reduction in postoperative stroke (adjusted odds ratio 0.09 [95% confidence interval 0.02 to 0.50]; p 0.005), and shorter postoperative hospital stay (p 0.001). Conclusions. coronary surgery is safe in patients with peripheral vascular disease, with acceptable results. The incidence of postoperative stroke is substantially reduced when avoiding cardiopulmonary bypass in patients with peripheral vascular disease. (Ann Thorac Surg 2004;77:1245 9) 2004 by The Society of Thoracic Surgeons Due to the improvement in outcomes following coronary artery bypass grafting (CABG) that have been achieved over the last two decades, a greater number of patients are being referred for CABG. Also, the patients undergoing CABG are more likely to be older, with a higher surgical risk [1, 2]. Patients with peripheral vascular disease (PVD) have a significantly higher risk of early postoperative adverse events following CABG [3 5]. Many studies have also shown that this subgroup of patients have poorer long-term survival after CABG [6 9]. In view of the significant early and long term mortality and morbidity risk in these patients undergoing CABG, and as they represent a significant percentage of patients (between 10% and 30% of most CABG populations) [7 9], strategies that may lead to a reduction in adverse outcomes in these patients will have a significant impact on Accepted for publication Sept 10, 2003. Address reprint requests to Dr Fabri, The Cardiothoracic Centre- Liverpool, Thomas Dr, Liverpool, L14 3PE UK; e-mail: brian.fabri@ctc. nhs.uk. resources and outcomes. This group of patients may benefit from off-pump CABG (OPCAB) [5]. We therefore analyzed our results of CABG to see if patients with PVD derived any benefit from OPCAB, while adjusting for differences in patient characteristics. Material and Methods Patient Population and Data Between 1 April 1997 and 31 March 2002, 3,771 consecutive patients underwent isolated coronary artery bypass surgery performed at two institutions (Cardiothoracic Center-Liverpool, and Manchester Royal Infirmary). Of these, 48% (n 1813) underwent OPCAB and 52% (n 1958) had on-pump CABG (ONCAB). Patients undergoing CABG that was incidental to heart valve repair or replacement, resection of a ventricular aneurysm, or other surgical procedure were not included. These patients represented the entire coronary revascularisation practice of five surgeons (DJMK, DMP, WCD, RH, and BMF). 2004 by The Society of Thoracic Surgeons 0003-4975/04/$30.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2003.09.054

1246 KARTHIK ET AL Ann Thorac Surg OPCAB IN PATIENTS WITH PVD 2004;77:1245 9 A total of 448 (11.9%) patients had documented PVD. The presence of peripheral vascular disease was defined in accord with The Society of Cardiothoracic Surgeons of Great Britain and Ireland minimum dataset [10]. This includes patients with a history of evidence of aneurysm or occlusive peripheral vascular disease, intermittent claudication, all patients who had been investigated and diagnosed to have PVD (including aortic and carotid artery disease), and all patients who had undergone intervention in the past (including aortic and carotid surgery). We have excluded 26 patients undergoing concomitant CABG and vascular surgery. Hence, our study group consisted of 422 patients with PVD. Details of the different surgical techniques used in these patients, OPCAB and ONCAB, have been published previously [11]. Overall, 211 (50.0%) patients received off-pump coronary surgery (94 without aortic manipulation, 117 with aortic manipulation), while 211 (50.0%) patients underwent ONCAB. Definitions and data collection methods have been previously published [12]. Data were collected prospectively during the patient s admission as part of routine clinical practice and entered into our cardiac surgery registry on the variables listed in Table 1 and Table 2. In-hospital mortality was defined as death within the same hospital admission regardless of cause. All patients transferred from the base hospital to another hospital were followed up to confirm their status at discharge. Reexploration for bleeding was defined as bleeding that required surgical reoperation after initial departure from the operating theater. Postoperative atrial arrhythmia was defined as the occurrence of new atrial arrhythmia in the absence of preoperative persistent or paroxysmal atrial arrhythmias. Postoperative stroke was defined as a new focal neurologic deficit and comatose states occurring postoperatively that persisted for more than 24 hours after its onset and was noted before discharge. We excluded confused states, transient events, and intellectual impairment from our study to avoid any subjective bias. Renal failure was defined as patients with a postoperative creatinine level greater than 200 mol/l or patients requiring dialysis. Postoperative myocardial infarction was defined as a new Q-wave postoperatively in two or more contiguous leads on an electrocardiogram, or significant rise in postoperative cardiac enzymes (creatine kinase-mb) combined with hemodynamic and echocardiographic signs of myocardial infarction. Deep sternal wound infection was defined in accord with the published evidence-based guidelines by the Centers for Disease Control and Prevention [13]. Gastrointestinal complications, which included gastrointestinal bleeding, pancreatitis, ischemic bowel, and perforation, were in line with the definitions of The Society of Cardiothoracic Surgeons of Great Britain and Ireland minimum dataset [10]. Table 1. Patient Characteristics Based on Procedure Performed p Value Age at operation 65.4 (59.3 72.2) 65.8 (58.5 70.8) 0.39 (years) Body mass index (kg/ 27.6 (24.6 30.5) 27.0 (25.1 29.9) 0.75 m 2 ) Female sex 23.2 (17.8 29.6) 18.0 (13.2 24.0) 0.19 NYHA class IV 6.2 (3.4 10.5) 9.5 (6.0 14.5) 0.20 Angina class IV 34.6 (28.3 41.5) 31.3 (25.2 38.1) 0.47 Previous MI 47.4 (40.5 54.3) 49.8 (42.8 56.7) 0.63 Diabetes 23.7 (18.2 30.1) 28.4 (22.6 35.1) 0.27 Hypercholesterolemia 84.8 (79.1 89.2) 79.2 (72.9 84.3) 0.13 Hypertension 66.8 (59.9 73.0) 55.9 (48.9 62.7) 0.022 Cerebrovascular 21.3 (16.1 27.6) 15.2 (10.7 20.9) 0.11 disease Renal dysfunction 8.5 (5.3 13.4) 3.8 (1.8 7.6) 0.043 Respiratory disease 27.0 (21.2 33.6) 26.5 (20.8 33.1) 0.91 Prior gastrointestinal 16.1 (11.6 21.9) 8.1 (4.9 12.8) 0.011 surgery Prior peptic 16.6 (11.9 22.4) 10.4 (6.8 15.6) 0.064 ulceration Ejection fraction 8.5 (5.3 13.3) 10.9 (7.2 16.1) 0.41 30% Three vessel disease 77.3 (70.9 90.1 (85.0 93.6) 0.001 82.6) Left main stenosis 23.2 (17.8 29.6) 23.2 (17.8 29.6) 0.99 Prior cardiac surgery 5.2 (2.8 9.4) 8.1 (4.9 12.8) 0.24 Emergent procedure 2.4 (0.9 5.7) 2.4 (0.9 5.7) 0.99 Number of grafts (n/ 3(2 3) 4 (3 5) 0.001 patient) LIMA use 90.1 (85.0 93.6) 82.9 (77.0 87.6) 0.033 EuroSCORE 6 (4 7) 6 (4 7) 0.58 Continuous variables are shown as median with 25th and 75th percentiles. Categorical variables are shown as a percentage with 95% confidence intervals. EuroSCORE European system for cardiac operative risk evaluation; LIMA left internal mammary artery; MI myocardial infarction; NYHA New York Heart Association. Statistical Methods Continuous variables are shown as median with 25th and 75th percentiles and categorical variables are shown as a percentage with 95% confidence intervals (CI). Comparisons were made with Wilcoxon rank sum tests and 2 tests as appropriate. Standard statistical tests were used to calculate odds ratios (OR) with 95% CI. The European System for Cardiac Operative Risk Evaluation (Euro- SCORE) was derived to assess differences in patient case mix between OPCAB and ONCAB patients [14]. Logistic regression was used to adjust in-hospital outcomes for differences in patient and disease characteristics (treatment selection bias) [15]. Treatment selection bias was controlled for by constructing a propensity score. The propensity score was the probability that a patient would receive OPCAB, and was constructed from the variables listed in Table 1 (C statistic 0.8) [17]. Once the propensity score is constructed for each patient, there are three ways of using the score for comparisons: matching,

Ann Thorac Surg KARTHIK ET AL 2004;77:1245 9 OPCAB IN PATIENTS WITH PVD 1247 Table 2. Crude Postoperative Data Based on Procedure Performed Odds ratio (95% confidence intervals) p Value In-hospital mortality 5.2 4.7 1.11 (0.46 2.66) 0.82 Myocardial infarction 2.8 2.4 1.21 (0.36 4.01) 0.76 Stroke 0.9 5.7 0.16 (0.04 0.72) 0.007 Atrial arrhythmia 31.7 22.3 1.62 (1.05 2.51) 0.028 Renal failure 7.1 9.0 0.77 (0.38 1.57) 0.47 Reexploration for bleeding 2.8 2.8 1.00 (0.32 3.15) 0.99 Sternal wound infection 1.9 2.4 0.79 (0.21 3.01) 0.74 Gastrointestinal compications 0.9 2.4 0.39 (0.07 2.05) 0.25 Postoperative stay 7 days 45.0 54.9 0.67 (0.46 0.98) 0.041 stratification, and multivariable adjustment. Due to the small sample size available to us for this study, we have decided to use multivariable adjustment, because matching would have reduced the study size even further and stratification can be difficult to interpret. The propensity score is then included along with the comparison variable (OPCAB or ONCAB) in multivariable analyses of outcome producing adjusted odds ratios, as shown in Table 3. The propensity score adjusts for the treatment selection bias, which is evident in Table 1, between one group and the other (eg, extent of disease, number of distal anastomoses, and hypertension). Using a propensity score as the sole means for adjusting outcomes was preferable, due to the low number of events in our study, and provides better adjustment for those factors driving treatment selection; the overall effect is more complete risk adjustment [16]. In all cases a p value less than 0.05 was considered significant. All statistical analyses were performed retrospectively with SAS for Windows Version 8.2. Results Table 1 lists patient and disease characteristics based on the procedure performed. In OPCAB patients, 13.3% (95% CI 9.1 to 18.8) had carotid disease compared to 8.1% (95% CI 4.9 to 12.8) in ONCAB patients (p 0.083). The incidence of aortic disease was also similar in the two groups. Patients receiving OPCAB were more likely to have hypertension (p 0.022), renal dysfunction (p 0.043), prior gastrointestinal surgery (p 0.011), and receive the left internal mammary artery (p 0.033). However, OPCAB patients had less extensive disease (p 0.001) and received fewer distal anastomoses (p 0.001). There was no significant difference between the groups with regard to the EuroSCORE risk profile (Table 1). CABG patients were more likely to have a shorter postoperative length of stay (median, 7 days [25th and 75th percentiles: 6 to 10]) compared to ONCAB patients (median, 8 days [25th and 75th percentiles: 7 to 11]; p 0.001). In-hospital outcomes by procedure performed are shown in Table 2 (crude) and Table 3 (adjusted for the propensity score). The propensity score included extent of disease, the number of distal anastomoses, use of the left internal mammary artery, cerebrovascular disease, renal dysfunction, and prior gastrointestinal surgery, which were identified as independent predictors of offpump group membership (C statistic 0.8). There was no association between avoiding cardiopulmonary bypass and in-hospital mortality, reexploration for bleeding, sternal wound infection, renal failure, gastrointestinal complications, and perioperative myocardial infarction in either univariate or multivariate analyses. CABG was associated with a significantly higher incidence of new atrial arrhythmias in the univariate analysis. However, after adjusting for the propensity Table 3. Postoperative Data Based on Procedure Performed Adjusted for the Propensity Score Odds ratio (95% confidence intervals) p Value In-hospital mortality 4.9 5.0 0.98 (0.35 2.75) 0.98 Myocardial infarction 2.5 2.6 0.96 (0.24 3.92) 0.96 Stroke 1.0 5.6 0.09 (0.02 0.50) 0.005 Atrial arrhythmia 29.1 24.4 1.39 (0.84 2.30) 0.21 Renal failure 6.7 9.6 0.59 (0.26 1.34) 0.21 Reexploration for bleeding 2.8 2.8 1.03 (0.27 3.95) 0.97 Sternal wound infection 1.6 2.7 0.50 (0.11 2.33) 0.38 Gastrointestinal complications 1.0 2.5 0.28 (0.04 1.79) 0.18 Postoperative stay 7 days 43.4 57.0 0.46 (0.29 0.74) 0.001

1248 KARTHIK ET AL Ann Thorac Surg OPCAB IN PATIENTS WITH PVD 2004;77:1245 9 score in the multivariate analysis this difference disappeared. The incidence of postoperative stroke was significantly lower in patients receiving OPCAB in both the univariate and multivariate analyses (adjusted OR 0.09, p 0.005). Fewer OPCAB patients had lengths of postoperative stay more than 7 days (adjusted OR 0.46, p 0.001). Comment One of the major changes that have occurred in the last 15 years is a rekindling of interest in OPCAB, as many believe that avoiding cardiopulmonary bypass could possibly lead to a further reduction in mortality and morbidity rates. The benefits of OPCAB are more likely to be seen in the high-risk cases, in which a significant part of the risk is believed to be associated with the need for cardiopulmonary bypass [18 20]. Patients with PVD are a major subgroup of patients undergoing CABG as these patients have a higher incidence of coronary artery disease. In fact, coronary artery disease is the leading cause of both early and late mortality following peripheral vascular revascularization [21, 22]. In our study, 448 patients out of a total of 3,771 (11.9%) had evidence of PVD. This compares well with several previous studies in which the prevalence of PVD in patients undergoing coronary artery revascularization has been between 10% and 30% [3, 8, 9]. The major difference in our study is the postoperative stroke rate, which was significantly lower in the OPCAB group (adjusted rate 1.0% vs 5.6%, p value 0.005). This was despite the fact that the incidence of carotid disease was higher in patients having OPCAB (13.3%) compared to those having ONCAB (8.1%). This inference is unchanged after risk adjusting with propensity score methodology [16], taking into account differences in extent of disease and other variables related to treatment selection bias. Another difference between the two groups was the significantly greater number of ONCAB patients who stayed longer than 7 days in-hospital following surgery. Stroke represents a particularly devastating complication following CABG. While its implications, both in terms of short-term and long-term consequences, to the patients are often devastating, it also has several major implications for health care providers, as it results in longer hospital and intensive care unit stay and places a significant strain on resources. Several recent studies have shown a significant reduction in the stroke rate following CABG with OPCAB [11, 23, 24]. Patients with PVD have been shown to have a significantly higher risk of perioperative events including death, myocardial infarction, and adverse neurologic outcomes [3, 5, 25]. The cause for stroke after conventional CABG is multifactorial. Among the various mechanisms involved are hemodynamic fluctuations, aortic manipulation, gas and particulate embolization, aortic clamping, arterial perfusion jets, and various other inflammatory and neurohumoral derangements associated with cardiopulmonary bypass [11, 18]. Patients with PVD often tend to have atheromatous involvement of all major arteries including the aorta and carotid arteries. These are likely to be associated with a higher incidence of thromboembolic episodes during cardiopulmonary bypass in these patients. Cannulation and aortic manipulation can also have disastrous consequences in these patients [25]. CABG offers a significant chance of reducing adverse neurologic outcomes following surgery as several of the risk factors mentioned above are evaded by avoiding aortic cannulation and cardiopulmonary bypass. There are some limitations, which may effect the conclusions drawn from this study. These include variables not measured in this study such as the quality of the coronary vessels, which is important in selecting the type of surgery and in determining the outcome, and selection bias resulting from the operating surgeon s decision to perform the procedure off-pump or on-pump. For this to effect our conclusions by a significant amount, the variables used in the propensity score would have to be uncorrelated with the variables not measured, but we do not believe that this is likely. This study also does not take into account pharmacological treatments and longterm outcomes for these patients (eg, antiplatelet drugs, graft patency, and quality of life). The additional graft received by our ONCAB patients might have a significant impact on longevity and reoperation rates. Another important limitation is that we have not taken into account the impact of aortic manipulation, although previously we have shown that aortic manipulation did not significantly alter neurologic outcome in our OPCAB series [11]. While we do not routinely practice epiaortic echocardiography to identify ascending aortic atherosclerotic disease, we do acknowledge that this subgroup of patients might benefit from epiaortic scanning. A further limitation is that the study is spread more than 5 years and most patients in the ONCAB group are from the early part of the study period, while most belonging to the OPCAB group are from the later part of the study period. Hence, they may represent two different patient populations. Also, the OPCAB group includes patients from the period during the learning curve of each surgeon, maybe indicating a degree of selection bias. However, we have compared the outcomes of the ONCAB patients of the five surgeons to their own OPCAB results, thus accounting for any variation due to the surgeon factor. Also, the two patient groups are well comparable in terms of patient characteristics and preoperative variables despite the temporal differences. In addition, we have used multivariate logistic regression analysis, incorporating these patient characteristics in a propensity score to account for any significant differences between the two groups. However, it is important to note that the propensity score cannot adjust for any changes that may have occurred in policy, which may influence our outcomes. In conclusion, we believe that this is the first study to compare the short-term outcomes of OPCAB with ON- CAB in patients with PVD. While it has not revealed any significant in-hospital survival benefit, it shows a highly

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