Coronary Bypass and Carotid Endarterectomy: Does a Combined Approach Increase Risk? A Metaanalysis

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1 ORIGINAL ARTICLES: CARDIOVASCULAR Coronary Bypass and Carotid Endarterectomy: Does a Combined Approach Increase Risk? A Metaanalysis Michael A. Borger, MD, Stephen E. Fremes, MD, Richard D. Weisel, MD, Gideon Cohen, MD, Vivek Rao, MD, PhD, Thomas F. Lindsay, MD, and C. David Naylor, MD, DPhil Divisions of Cardiovascular Surgery and Vascular Surgery, The Toronto Hospital; and the Division of Cardiovascular Surgery, and Institute for Clinical Evaluative Sciences, Sunnybrook and Women s College Health Sciences Center; University of Toronto, Toronto, Ontario, Canada Background. Patients with concomitant carotid and coronary artery disease present a surgical dilemma. We compared the stroke and mortality rates for combined coronary artery bypass grafting and carotid endarterectomy in which both procedures were performed under a single anesthetic, versus a staged approach, in which coronary artery bypass grafting and carotid endarterectomy were performed separately. Methods. A computerized MEDLINE search supplemented with a manual bibliographic review was performed for all peer-reviewed English language publications that contained both combined and staged coronary artery bypass grafting/carotid endarterectomy patient cohorts. Outcomes of interest were stroke, death, and stroke or death; aggregation of outcome rates was performed with the Mantel-Haenszel method. Results. Sixteen studies were identified with a total of 844 combined patients and 920 staged patients. None of the studies was completely randomized. The combined surgical group had a higher prevalence of unstable angina; the two groups had a similar prevalence of symptomatic carotid disease and severe carotid stenosis. Metaanalysis revealed a significantly increased risk of the composite end point, stroke or death, for patients undergoing combined procedures (relative risk 1.49; 95% confidence interval ; p 0.034). There was also a trend toward increased risk during combined procedures for the end points of stroke (relative risk 1.50; 95% confidence interval ; p 0.068) and death (relative risk 1.55; 95% confidence interval ; p 0.084) considered separately. The crude event rates for stroke were 6.0% versus 3.2% for combined versus staged procedure, 4.7% versus 2.9% for death, and 9.5% versus 5.7% for stroke or death. Two of the 16 individual studies showed a statistically significant increase in the risk of stroke or death for combined procedure (p < 0.05). Conclusions. Combined coronary artery bypass grafting and carotid endarterectomy may be associated with a higher risk of stroke or death than staged procedures. A randomized trial needs to be performed to determine the optimal management of patients with concomitant carotid and coronary artery disease. (Ann Thorac Surg 1999;68:14 21) 1999 by The Society of Thoracic Surgeons The current indications for surgical revascularization of isolated carotid or coronary artery disease are well described. Recent randomized clinical trials demonstrate that carotid endarterectomy (CEA) decreases stroke risk in patients with symptomatic [1, 2] and, to a lesser extent, asymptomatic [3] severe carotid stenosis. The indications for coronary artery bypass grafting (CABG) are well defined in the cardiac surgery literature [4]. However, the optimal management of patients with concomitant coronary and carotid vascular disease is not known. The importance of this clinical problem is accentuated by the finding that patients frequently present with atherosclerosis of both arterial systems: 8% to 14% Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25 27, Address reprint requests to Dr Fremes, Sunnybrook Health Science Centre, Rm H405, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5. of CABG patients have significant carotid stenosis [5, 6] and 40% to 50% of CEA patients have coronary artery disease [7, 8]. The treatment options for a patient presenting with concomitant surgical carotid and coronary artery disease include combined CABG/CEA (both procedures performed under a single anesthetic) and staged CABG/ CEA (CEA performed before CABG as a separate procedure, or vice versa). Several proponents exist for both types of surgical approaches with published case series proclaiming the safety of each technique. The relative risk associated with either approach is not known, however, because the majority of case series focus on only one treatment modality and because the number of patients in each study is relatively small. The purpose of this study, therefore, is to determine the relative risk of stroke and mortality for combined versus staged CABG/ CEA using a systematic review of the literature by The Society of Thoracic Surgeons /99/$20.00 Published by Elsevier Science Inc PII S (99)

2 Ann Thorac Surg BORGER ET AL 1999;68:14 21 CORONARY BYPASS AND CAROTID ENDARTERECTOMY 15 Table 1. Selection Criteria and Prevalence of Risk Factors for Combined and Groups Study (first author) Intervention Selection Criteria Carotid Risk Factors Cardiac Risk Factors Symptomatic Severe Contralateral UAP LV Dysfxn 3 VD LM Reop Bernhard [15] Comb Changed over time 84% of all pts... 68% of all pts... 13% Changed over time % Urschel [16] Comb Severe lesion of both systems 74% of all pts... 35% of all pts 26% of all pts 26% of all pts 29% of all pts 26% of all pts... Mehigan [17] Comb Severe lesion of one system (operated on first) Unstable angina or stable angina with severe CAD % of all pts... 10% 48% 14% of all pts 69% of all pts 16% of all pts... Stable angina without severe CAD... 15% 0%... Hertzer [18] Comb Date of operation after %... 42% 30% 4% 57%... Date of operation 1973 or earlier 14%... 40% 32% 0% 47% Ennix [19] Comb Not stated 52% of all pts... 38% of all pts 28% of all pts 19% of all pts 46% of all pts 19% of all pts... Not stated Berkoff [20] Comb Severe lesion of both systems 90% of all pts 100% 33% of all pts 33% of all pts 5% of all pts 57% of all pts 19% of all pts... Severe lesion of one system (operated on first) 100% Rosenthal [21] Comb Unstable cardiac disease % (?) Stable angina % (?) Ivey [22] Comb Not stated 100% Not stated 100% Newman [23] Comb Severe lesion of both systems 88% of all pts 84% of all pts 44% of all pts 54% of all pts 8% of all pts 52% of all pts 24% of all pts... Severe lesion of one system (operated on first) Hertzer [24] Comb Randomization of selected patients (see text) Randomization of selected patients (see text) 46% 95% of all pts 0% 49% of all pts 72% of all pts 81% of all pts 23% of all pts 7% of all pts 31% 0% Faggioli [25] Comb Not stated 0% 100% Not stated 0% 100% Carrel [26] Comb Not stated 77%... 15% 33% 12% 42% 33%... Not stated Coyle [27] Comb Unstable cardiac status 57%... 14% of all pts 39% of all pts % of all pts Stable cardiac status 49% Giangola [28] Comb Not stated 82% % Not stated 69% % Takach [29] Comb Unstable angina 37% 98% 33% 31% 30%... 29% 13% Stable angina 40% 98% 34% 6% 19%... 25% 9% Peric [30] Comb Not stated 54%... 29% 67% 35% 100% 35%... Not stated 62%... 29% 35% 16% 100% 16%... CAD coronary artery disease; Comb combined group; LM left main coronary artery disease; LV Dysfxn left ventricular dysfunction; pts patients; Reop reoperation; staged group; UAP unstable angina pectoris; 3VD triple-vessel coronary artery disease;... information not given.

3 16 BORGER ET AL Ann Thorac Surg CORONARY BYPASS AND CAROTID ENDARTERECTOMY 1999;68:14 21 Material and Methods A comprehensive literature review was undertaken using a MEDLINE search of coronary bypass surgery and carotid endarterectomy from 1980 to August 1998, supplemented with manual bibliography reviews. All peer-reviewed studies published in the English language that dealt with concomitant carotid and coronary artery procedures were identified and reviewed. Studies containing data that was duplicated in latter publications from the same institution [9 11] and studies that did not separate results for combined and staged CABG/CEA patient cohorts [12 14] were excluded. Sixty-seven publications were identified that reported results from patients undergoing combined operations and 19 publications reported the results of staged procedures. The median date of publication was 1992 for combined studies and 1987 for staged studies. To minimize temporal bias, as well as interinstitutional variability, studies were included in the metaanalysis only if they contained both combined and staged patient cohorts. Sixteen studies [15 30] were identified using this literature search technique (Table 1). All data were extracted from the studies and entered into a computer file. The prespecified study end points were (1) the composite end point of stroke or death, and (2) the incidence of stroke or death considered separately. Secondary study end points were (1) incidence of myocardial infarction, and (2) incidence of myocardial infarction, stroke, or death. It should be stressed that with one partial exception [24], none of the studies are randomized clinical trials; they are all retrospective observational studies of cohorts of consecutive patients with concomitant carotid and coronary artery disease. The study by Hertzer and colleagues [24] included randomization of a subset of patients to a combined or a staged approach (see below). Fisher s exact test was used for study-specific relative risk calculations. Aggregation of the overall rates of stroke, death, and stroke or death for combined versus staged operations was performed with the Mantel- Haenszel 2 test. Yate s correction was used for those studies that contained a zero in one cell for the number of events of interest (ie, studies with no strokes/deaths for one of the treatment groups). Those studies that contained a zero in two cells (ie, no strokes/deaths for both treatment groups) were excluded from the analysis: three papers [16, 23, 25] were excluded for the analysis of death rates for this reason, two papers [21, 25] were excluded for the analysis of stroke rates, and one paper [25] was excluded from the analysis of stroke or death rates. Table 2. Summary of Metaanalysis for Primary Outcomes Outcome Relative Risk 95% CI p Value p Value Homogeneity Stroke Death Stroke or death Relative risks greater than 1.0 indicate increased risk for combined procedures. CI Confidence interval. Table 3. Crude Event Rates of Primary Outcomes for Individual Studies Study (first author) Statistical analysis was performed using commercially available software (Epistat, Epistat Services, Richardson, TX; and SAS, SAS Institute Inc, Cary, NC). Results Intervention No. of Patients Stroke (%) Death (%) Stroke or Death (%) Bernhard [15] Comb 15 2 (13.3) 0 (0) 2 (13.3) 16 2 (12.5) 5 (31.3) 7 (43.8) Urschel [16] Comb 7 0 (0) 0 (0) 0 (0) 24 1 (4.2) 0 (0) 1 (4.2) Mehigan [17] Comb 21 2 (9.5) 1 (4.8) 3 (14.3) 20 0 (0) 0 (0) 0 (0) Hertzer [18] Comb (8.7) 5 (4.3) 15 (13.0) 59 3 (5.1) 1 (1.7) 4 (6.8) Ennix [19] Comb 51 1 (2.0) 3 (5.9) 4 (7.8) 84 1 (1.2) 1 (1.2) 2 (2.4) Berkoff [20] Comb 16 1 (6.3) 1 (6.3) 2 (12.5) 5 1 (20.0) 0 (0) 1 (20.0) Rosenthal [21] Comb 24 0 (0) 0 (0) 0 (0) 22 0 (0) 1 (4.5) 1 (4.5) Ivey [22] Comb 4 1 (25.0) 1 (25.0) 1 (25.0) 5 0 (0) 0 (0) 0 (0) Newman [23] Comb 10 1 (10.0) 0 (0) 1 (10.0) 40 0 (0) 0 (0) 0 (0) Hertzer [24] Comb (5.3) 7 (5.3) 11 (8.4) (11.4) 4 (3.8) 14 (13.3) Faggioli [25] Comb 2 0 (0) 0 (0) 0 (0) 17 0 (0) 0 (0) 0 (0) Carrel [26] Comb 52 1 (1.9) 2 (3.8) 3 (5.8) 45 0 (0) 2 (4.4) 2 (4.4) Coyle [27] Comb (15.4) 7 (10.8) 13 (20.0) 45 2 (4.4) 1 (2.2) 3 (6.7) Giangola [28] Comb 28 4 (14.3) 0 (0) 4 (14.3) 29 1 (3.4) 2 (6.9) 2 (6.9) Takach [29] Comb (3.9) 10 (3.9) 18 (7.1) (1.9) 4 (1.6) 8 (3.1) Peric [30] Comb 48 1 (2.1) 3 (6.3) 3 (6.3) (0.7) 6 (4.1) 7 (4.8) Totals Comb (6.0) 40 (4.7) 80 (9.5) (3.2) 27 (2.9) 52 (5.7) Comb combined group; staged group. The 16 studies identified included a total of 844 patients in the combined group and 920 patients in the staged group. Operative techniques for patients undergoing combined operation were similar for all studies, with CEA being performed before CABG under the same anesthetic, except for Ennix and colleagues [19], where the sequence of operations was not stated (Appendix). Operative techniques for patients undergoing staged procedures varied between studies the sequence of operations consisted of CEA before CABG in eight studies, CABG before CEA in one study, and a mixture of the two approaches in the remaining seven studies (Appen-

4 Ann Thorac Surg BORGER ET AL 1999;68:14 21 CORONARY BYPASS AND CAROTID ENDARTERECTOMY 17 Fig 1. Relative risks (vertical lines) 95% confidence intervals (horizontal lines) for stroke in combined versus staged coronary artery bypass grafting/carotid endarterectomy. Values greater than 1.0 indicate increased risk for combined procedures. Note that the x-axis is logarithmic. dix). No attempt was made to stratify staged patients according to operative technique because of lack of detailed information on outcomes within these groups, and because of the small number of adverse events. Table 1 summarizes selection criteria for combined and staged groups for each study. Selection criteria were not stated or ambiguously defined in 8 of the 16 studies. Seven studies stated that those patients with severe lesions of both carotid and coronary arterial systems or patients with unstable cardiac symptoms were treated with a combined approach, whereas patients with a severe lesion of only one system were treated with a staged approach. The study by Hertzer and associates [24] randomized 129 patients with asymptomatic carotid stenosis and high cardiac risk into a combined group (n 71) and a staged group (CABG performed before CEA, n 58). Also included in this study, however, were three nonrandomized groups: a group of patients with low cardiac risk who underwent staged operation (CEA before CABG, n 24), and two groups of patients with high cardiac risk and symptomatic carotid disease who underwent either combined (n 60) or staged operation (CABG before CEA, n 23). The selection criteria for combined versus staged operation for these last two groups of patients were not defined. Table 1 also displays the prevalence of known carotid and cardiac risk factors for combined and staged groups for each study. The majority of studies either did not contain risk factor information or reported risk factor prevalence for all patients, without distinguishing between combined and staged groups, thereby making statistical analysis of possible unbalance covariates difficult. In those studies in which detailed reporting was available, however, there was no significant difference in the prevalence of symptomatic carotid disease (47% for combined group versus 46% for staged group) or severe (more than 70%) carotid stenosis (97% for both groups). A significantly higher proportion of patients undergoing combined operation had unstable angina (37% versus 21%, p 0.001). Stroke Table 2 displays the metaanalysis results for each of our primary outcomes. Metaanalysis revealed a trend toward increased risk of stroke during combined surgery (relative risk 1.50; 95% confidence interval ; p 0.068). Table 3 displays the crude event rates for all primary outcomes. The incidence of stroke was 6.0% for combined operations versus 3.2% for staged procedures. Figure 1 shows the study-specific relative risks for stroke for each of the 14 studies included in the metaanalysis (as mentioned above, two studies were dropped in the analysis of stroke rates because both treatment groups had zero strokes). Twelve of the 14 studies showed an increased incidence of stroke for combined operations (relative risk 1.0), but none was statistically significant. Fig 2. Relative risks (vertical lines) 95% confidence intervals (horizontal lines) for death in combined versus staged coronary artery bypass grafting/carotid endarterectomy. Values greater than 1.0 indicate increased risk for combined procedures. Note that the x-axis is logarithmic. Fig 3. Relative risks (vertical lines) 95% confidence intervals (horizontal lines) for stroke or death in combined versus staged coronary artery bypass grafting/carotid endarterectomy. Values greater than 1.0 indicate increased risk for combined procedures. Note that the x-axis is logarithmic.

5 18 BORGER ET AL Ann Thorac Surg CORONARY BYPASS AND CAROTID ENDARTERECTOMY 1999;68:14 21 Death Metaanalysis revealed a nonsignificant trend toward increased risk of death during combined procedures (Table 2; relative risk 1.55; 95% confidence interval ; p 0.084). The crude mortality rate was 4.7% for combined procedures versus 2.9% for staged procedures (Table 3). Study-specific relative risks for death are displayed in Figure 2. Nine of the 13 studies included in this analysis showed an increased incidence of death for combined operations, but none was statistically significant. Stroke or Death Table 2 displays a significantly increased risk of stroke or death during combined operations by metaanalysis (relative risk 1.49; 95% confidence interval ; p 0.034). Crude event rates for stroke or death were 9.5% for combined procedures versus 5.7% for staged operation (Table 3). Figure 3 displays the relative risks of stroke or death for combined versus staged CABG/CEA. Eleven of the 15 studies included in this analysis showed an increased adverse event rate for combined procedures, with two being statistically significant (Coyle [27] and Takach [29] and their colleagues). Secondary Outcomes Table 4 displays the crude event rates of our secondary outcomes myocardial infarction and the composite end point of myocardial infarction, stroke, or death. The crude event rate of fatal or nonfatal myocardial infarction was 4.6% for combined operation and 5.2% for staged operation. Metaanalysis revealed no significant difference in the risk of myocardial infarction between the two operative techniques (relative risk 0.74; 95% confidence interval ; p 0.207). Unfortunately, only 9 of the 16 studies reported individual patient information for the composite end point of myocardial infarction, stroke, or death. This resulted in a loss of data on the majority of patients (1,281 of 1,762 patients); therefore, precluding a meaningful analysis of this end point. Table 4. Crude Event of Secondary Outcomes for Individual Studies Study (first author) Intervention No. of Patients MI (%) MI, Stroke, or Death (%) Bernhard [15] Comb 15 0 (0) 2 (13.3) 16 3 (18.8) 7 (43.8) Urschel [16] Comb 7 0 (0) 0 (0) 24 1 (4.2) 2 (8.3) Mehigan [17] Comb 21 1 (4.8) 3 (14.3) 20 0 (0) 0 (0) Hertzer [18] Comb (10.4) Not stated 59 6 (10.2) Not stated Ennix [19] Comb 51 3 (5.9) Not stated 84 1 (1.2) Not stated Berkoff [20] Comb 16 0 (0) 2 (12.5) 5 0 (0) 1 (20.0) Rosenthal [21] Comb 24 0 (0) 0 (0) 22 1 (4.5) 1 (4.5) Ivey [22] Comb 4 0 (0) 1 (25.0) 5 0 (0) 0 (0) Newman [23] Comb 10 0 (0) 1 (10.0) 40 0 (0) 0 (0) Hertzer [24] Comb 131 Not stated Not stated 105 Not stated Not stated Faggioli [25] Comb 2 Not stated Not stated 17 Not stated Not stated Carrel [26] Comb 52 1 (1.9) Not stated 45 4 (8.9) Not stated Coyle [27] Comb 65 Not stated Not stated 45 Not stated Not stated Giangola [28] Comb 28 0 (0) 4 (14.3) 29 5 (17.2) 6 (20.7) Takach [29] Comb (4.7) Not stated (4.7) Not stated Peric [30] Comb 48 1 (2.1) 4 (8.3) (4.1) 10 (6.8) Comb combined group; MI Myocardial infarction; staged group. Comment The indications for isolated CABG and CEA are well defined [1 4]. The optimal management of patients with concomitant surgical disease of both arterial systems is controversial, however, with some experts advocating staged operation and some recommending a combined approach. The relative risk of these two surgical techniques is not known. Therefore, we undertook this comprehensive literature review to compare morbidity and mortality of combined versus staged CABG/CEA. We identified 16 studies with combined and staged patient cohorts, and in general found a higher risk of adverse outcomes for combined operation. Metaanalysis revealed a statistically significant increase in risk of stroke or death. Examination of each study separately revealed that the majority demonstrated increased risk for combined procedures, two were statistically significant. Crude event rates for each adverse outcome were also higher for combined operation. As expected, these event rates are higher than those associated with isolated CABG or isolated CEA [1, 31]. Before concluding that combined operation results in increased risk, however, it is important to consider that none of the studies analyzed were completely randomized trials. Therefore, selection bias may have resulted in unequal distribution of higher risk patients. Indeed, review of selection criteria for each study revealed that many studies used a combined approach in patients with severe lesions of both arterial systems, which may have resulted in greater atherosclerotic burden in the combined group. If combined procedure does indeed result in a higher risk of stroke or death compared to staged operation, there are several possible reasons. One reason may be that combined procedures are more technically difficult, from both a surgical and an anesthetic point of view, than

6 Ann Thorac Surg BORGER ET AL 1999;68:14 21 CORONARY BYPASS AND CAROTID ENDARTERECTOMY 19 staged procedures resulting in more perioperative complications. Another reason may be that combined operations result in excessive stress on the cardiovascular and cerebrovascular systems, resulting in large fluctuations in patient hemodynamics during relatively long operative procedures. Finally, differences in coagulation management during combined procedures may increase the risk of thrombosis, particularly as antifibrinolytics are commonly used in CABG. An important secondary end point of this study was myocardial infarction. We did not find a difference in risk of myocardial infarction for the two groups of patients. It has been traditionally thought that staged procedures (CEA before CABG) may result in a higher risk of myocardial infarction, particularly in the perioperative period of the carotid operation. Our finding of no increased risk of myocardial infarction for staged operation lends further support to the safety of this surgical approach. It should be noted that the partially randomized study by Hertzer and colleagues [24] demonstrated a higher incidence of stroke during staged procedure in the 129 randomized patients (14% versus 3%). It may be argued that the high incidence of stroke was attributable to the sequence of operations in the staged group, with CABG being performed before CEA. Indeed, a previous review of the literature revealed a very high incidence of stroke in patients undergoing such reverse-staged procedures [32]. The optimal surgical approach for staged procedures may be, therefore, CEA before CABG. To the best of our knowledge, only one previous metaanalysis has examined the issue of combined and staged CABG/CEA [32]. In contrast to our study, Brener and associates demonstrated an increased risk of myocardial infarction and death in patients undergoing staged procedures, with no difference in stroke rates. One large difference exists between the metaanalysis performed by them and our study, which may explain our discrepant findings. Brener and colleagues analyzed all studies that contained patients undergoing either combined or staged CABG/CEA, whereas we examined only those studies that contained both combined and staged patient cohorts from the same institution. A larger proportion of papers examining the results of combined operation has been published in more recent years when compared with staged surgical papers (median date of publication 1992 for combined studies versus 1987 for staged studies). This may result in a temporal bias because of the well documented decreases in morbidity and mortality for cardiac surgery over time [33 35]. We believe the inclusion of papers with both combined and staged patient cohorts will minimize temporal bias, as the time period of operations was the same for combined and staged patients for each individual study. In addition, the inclusion of combined and staged cohorts from the same institution would presumably result in the same surgeons performing each operative strategy, thereby minimizing operator and center-specific effects including differences in case selection and operator skill. Limitations of Study The main limitation of our metaanalysis is that none of the studies that we analyzed, with the partial exception of one, were randomized clinical trials. Randomized clinical trials would have been obviously preferable to retrospective case series [36], because they allow relatively unbiased within-study estimations of effects that can be aggregated using standard metaanalytic techniques [37, 38]. To determine definitively whether staged operation results in better outcomes than combined procedure, a randomized clinical trial must be performed. Such a study would require a multiinstitutional, multinational effort to achieve the appropriate sample size. For example, using stroke or death as the primary outcome with an expected incidence of 7.5% (the overall incidence of stroke or death was 7.5% for both groups in this comprehensive review), a sample size of 1,500 patients per group would be required to detect a relative risk reduction of 33% with an level of 0.05 and a power of 80%. As patients with concomitant carotid and coronary artery disease represent a high-risk surgical group, the appropriateness of carotid angioplasty and stenting for this population should also be addressed [39]. 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Incorporating variations in the quality of individual randomized trials into metaanalysis. J Clin Epidemiol 1992;45: Naylor CD. Meta-analysis and the meta-epidemiology of clinical research. BMJ 1997;315: Dorros G. Stent-supported carotid angioplasty: should it be done, and if so, by whom? A 1998 perspective. Circulation 1998;98: Appendix Study (first author) Sequence of Operations Combined a Bernhard [15] Urschel [16] Mixed approach 29% Mehigan [17] Hertzer [18] Ennix [19] Not stated CABG then CEA Berkoff [20] Mixed approach 50% Rosenthal [21] Mixed approach 64% Ivey [22] Newman [23] Mixed approach 70% Hertzer [24] Mixed approach 23% Faggioli [25] Carrel [26] Coyle [27] Giangola [28] Mixed approach 59% Takach [29] Peric [30] Mixed approach 66% a Sequence of operations for combined procedures indicates the order of procedures performed while under one anesthetic. CABG coronary artery bypass grafting; CEA carotid endarterectomy.