A systematic review of outcome following synchronous carotid endarterectomy and coronary artery bypass: Influence of surgical and patient variables

Eur J Vasc Endovasc Surg 26, 230±241 (2003) doi: 10.1016/S1078-5884(03)00247-8, available online at http://www.sciencedirect.com on

REVIEW

A Systematic Review of Outcome Following Synchronous Carotid Endarterectomy and Coronary Artery Bypass: Influence of Surgical and Patient Variables R. Naylor1, R. L. Cuffe2, P. M. Rothwell2, I. M. Loftus1 and P. R. F. Bell1 1

The Department of Vascular Surgery at Leicester Royal Infirmary and 2The University Department of Clinical Neurology, The Radcliffe Infirmary, Oxford, U.K.

Objectives: outcomes after synchronous carotid endarterectomy (CEA) plus coronary artery bypass (CABG) relative to surgical and patient based variables. Design: systematic review of 94 published series (7863 synchronous procedures). Results: 11.5% of patients died or suffered a stroke/myocardial infarction in the peri-operative period (95% CI 10.1±12.9). The risk of death/stroke appeared to significantly diminish in studies published between 1993±2002, compared with 1972± 1992 (7.2% (95% CI 6.5±9.1) versus 10.7% (95% CI 8.9±12.5), p ˆ 0.03). However, increasing operative experience was not associated with significantly lower risks of death/stroke; (1±49 cases (9.6% (95% CI 7.5±11.8); 50±99 cases (9.1% (95% CI 6.4±11.8); 100 ‡ cases (8.4% (95% CI 6.9±10.1) (p ˆ 0.64)). Patients with severe bilateral carotid disease were significantly more likely to suffer death and/or stroke compared to patients with unilateral disease (odds ratio 2.5, 95% CI 1.4±5.0, p ˆ 0.001). Similarly, patients with a prior history of stroke/transient ischaemic attack (TIA) were significantly more likely to suffer a further stroke than asymptomatic patients (odds ratio 1.8, 95% CI 1.1±2.8, p ˆ 0.008). There was no difference in the risk of death/stroke relative to the timing of CEA (pre- versus on-cardiopulmonary bypass), but recent small studies indicate that improved outcomes might be achieved by performing CABG `off-bypass'. Conclusions: synchronous CEA ‡ CABG is associated with a not insignificant cardiovascular risk. No comparable information is available for similar patients undergoing CABG without prophylactic CEA. Key Words: Carotid endarterectomy; Coronary bypass; Stroke; Staged; Synchronous.

Introduction A recent systematic review compared outcomes following staged CEA-CABG, reverse staged CABGCEA and synchronous CEA ‡ CABG in patients with coronary and carotid artery disease.1 The main observation was that there were no statistically significant differences in outcome regarding death, ipsilateral stroke, any stroke, and death/stroke. This review did not, however, undertake any subgroup analyses because of the relatively small numbers of patients undergoing staged CEA-CABG and staged CABG-CEA. The current paper focuses on a series of subgroup analyses of 7863 patients undergoing synchronous  Please address all correspondence to: Ross Naylor, Department of Vascular Surgery, Clinical Sciences Building, P. O. Box 65, Leicester Royal Infirmary, Leicester, U.K.

CEA ‡ CABG. The aim was to identify factors associated with adverse outcome. Subgroups included (i) neurological status prior to surgery, (ii) extent of carotid disease (unilateral, bilateral), (iii) timing of publication (1972±1992, 1993±2002), (iv) bilateral CEA and CABG, (v) number of cases reported and (vi) the timing of CEA with respect to cardiopulmonary bypass (CPB).

Materials and Methods The search strategy and statistical methods were identical to those employed previously.1 Studies were identified by manual journal review (European Journal of Vascular and Endovascular Surgery, Journal of Vascular Surgery, Annals of Vascular Surgery, Stroke, Annals of Thoracic Surgery, Journal of Thoracic and

1078±5884/03/030230‡12 $35.00/0 # 2003 Elsevier Science Ltd. All rights reserved.

Systematic Review of Outcome

Cardiothoracic Surgery), cross-referencing and an electronic PUBMED search using the advanced option. A combination of search terms was used including `carotid endarterectomy', `carotid surgery', `coronary surgery', or `bypass surgery' in combination with one of `stroke', `carotid' or `cardiac' as appropriate. Studies were included if published between January 1972 and June 2002 inclusive. Patients undergoing valve repair or carotid reconstruction other than endarterectomy (e.g. aorto-carotid bypass) were excluded. One hundred and nine series were identified.2±110 Fifteen were excluded.96±110 Reasons included; inability to obtain a copy of the manuscript,96 while nine were subsequently updated with larger numbers.97±105 If, however, any included data useful for subgroup analyses (i.e. not in the updated paper), these were included in the analysis. In four studies it was not possible to differentiate staged from synchronous procedures.106±109 The remaining study110 was excluded because it contained fewer patients than a similar series from the same centre published one year earlier.61 Ninety-four studies2±95 describing the outcome following 7863 synchronous procedures were included in the systematic review. Demographic data included; (i) pre-operative neurological status (asymptomatic or symptomatic carotid disease irrespective of timing or laterality to the synchronous procedure), (ii) the presence of unilateral or bilateral carotid disease, (iii) whether the CABG was performed `urgently' e.g. for unstable angina, (iv) the prevalence of left mainstem coronary artery disease and (v) the proportion of patients deemed to be NYHA class III or IV for cardiac disease. Other data included year of publication (1972±1993 vs. 1994± 2002), the number of cases reported in the series (1± 49, 50±99, 100 ‡ ) and when CEA was performed with respect to CPB (pre-bypass, on-bypass or off-bypass). Operative events included any end-point occurring 530 days of synchronous CEA ‡ CABG. Most studies documented events occurring 530 days. Others only recorded `in-hospital' events. For the purpose of this review, the two have been combined. It is accepted that this may under-report the true risk, but this cannot be avoided. Endpoints included; (i) death, (ii) any stroke, (iii) stroke ipsilateral to the CEA and (iv) myocardial infarction (MI). Unfortunately, there was no systematic method for diagnosing peri-operative MI during the 30-year period of the review (serial ECG and/or enzyme changes) and many studies did not document MI. Most were probably diagnosed following acute clinical deterioration. The remaining endpoints included: (v) death/ipsilateral CVA, (vi) death/ any CVA and (vii) death/any CVA/MI. Not all papers

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reported this information and hence, the denominator may not be the same as the total number of patients in the meta-analysis. A statistician (RLC) performed all analyses and the data were analysed in two formats. In the first, the actual observed risks were estimated by combining all the studies that reported data on that particular endpoint. No statistical comparisons could be performed on these results. However, heterogeneity and 95% confidence intervals (95% CI) were determined. In those analyses where there was significant heterogeneity, 95% CIs were expanded to account for extrabinomial variation arising from the differences in risk between studies.111 Calculating the weighted sum of squared deviations from the estimate assessed the heterogeneity of the actual risk. This statistic was then compared to a chi-squared distribution to produce the p-values listed in the tables.112 The second method allowed for within-group statistical analyses to be performed (e.g. asymptomatic versus symptomatic, unilateral vs. bilateral carotid disease). Using this approach, only studies reporting outcomes for both subgroups were included. MantelHaenzal estimates of the odds ratio113 were determined along with measurements of heterogeneity and 95% confidence intervals. In the latter analysis, confidence intervals for the odds ratio were determined using Miettinen's test based formula.114 Measurement of heterogeneity enables the reader to gauge whether the pooled/calculated risks are measuring the same thing. Statistically significant heterogeneity (p 5 0.05) in estimates between studies indicates that the overall variation in the reported risk is greater than would be expected by chance. This could be due to differences in case-mix, operative technique or other factors. Alternatively, p 4 0.05 indicates that there is no significant heterogeneity and that each study was reporting a similar outcome or trend. Results Summary of principal results Tables 1 and 2 review the demographics and overall outcomes for synchronous CEA ‡ CABG that were published in the first review.1 Approximately 60% of synchronous procedures were undertaken in patients with asymptomatic carotid artery disease, while the majority (62%) had unilateral 50±99% stenoses. The indication for cardiac surgery was classed as `urgent' in 39%, 25% had significant left main stem disease and 72% were NYHA grade 3 or 4. The operative mortality (Table 2) was 4.6% (95% CI 4.1±5.2). The risk of stroke Eur J Vasc Endovasc Surg Vol 26, September 2003

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was 4.6% (3.9±5.4), while the risk of ipsilateral stroke was 3.0% (95% CI 2.4±3.5). The risk of MI was 3.6% (95% CI 3.0±4.2). The `30-day' risk of death/ipsilateral stroke was 7.4% (95% CI 6.5±8.3). The risk of death/ any stroke was 8.7% (95% CI 7.7±9.8). The risk of death/stroke/MI was 11.5% (95% CI 10.1±12.9). Causes of death within 30 days of surgery Table 3 lists the causes of death in 267 patients after 5747 synchronous procedures. The commonest cause of death was cardiac (50%). Others included sepsis/ multi-organ failure (22%), stroke (17%), miscellaneous (8%) and `bleeding' complications (3%). Of those dying a cardiac death, the principal causes were acute MI, cardiac failure/cardiogenic shock and arrhythmia. It was not possible to reliably comment on the laterality of fatal strokes after synchronous CEA ‡ CABG as this was not specified in the majority of reports.

symptomatic or asymptomatic at the time of surgery (Table 4). Unfortunately, no data were forthcoming regarding the timing, severity or laterality of the preceding TIA/stroke as this was virtually never documented. Overall, patients with a prior history of TIA/ stroke seemed to encounter worse outcomes than asymptomatic patients. The data in Table 4 cannot, however, be compared statistically. To do this, studies reporting outcomes for both symptomatic and asymptomatic patients were identified (Table 5). Note, however, that the observed risks were actually very nearly identical to those detailed in Table 4 (the entire series). Although there were trends towards worse outcomes in symptomatic patients, there were no statistically significant differences for death, ipsilateral stroke or death/any stroke. However, the fact that the heterogeneity was 40.05 in each of these categories

Asymptomatic vs. symptomatic carotid stenosis? Forty-two series (2207 patients) published outcomes according to whether the patient was neurologically Table 1. Demography on patients undergoing synchronous CEA ‡ CABG. Symptomatic carotid stenosis  Asymptomatic carotid stenosis  Unilateral 50±99% stenosis  Bilateral 50±99% stenosis/occlusion  `Urgent' CABG  Left mainstem disease NYHA grade 3 or 4

2830/6827 41.1% (95% CI 37.4±44.9) 4048/6878 59.3% (95% CI 55.6±63.0) 3826/6137 62.3% (95% CI 58.6±66.1) 2261/6137 36.8% (95% CI 32.9±40.8) 1675/4287 39.1% (95% CI 33.9±44.2) 1240/5017 24.7% (95% CI 21.5±27.9) 885/1231 71.9% (95% CI 65.1±78.7)

 Some papers did not provide all of this information and hence the denominator will not be the same as the total number of patients in the meta-analysis.

Table 3. Causes of 267 deaths following 5747 synchronous CEA ‡ CABG. Cardiac Myocardial infarction Cardiac failure/cardiogenic shock Arrhythmia Graft haemorrhage Myocardial rupture Graft thrombosis Coronary `spasm' Cardiac cause not specified Stroke Ipsilateral Non-ipsilateral Intracranial haemorrhage Laterality not specified

134 39 37 15 2 1 1 1 38 44 14 5 1 24

Bleeding complications Generalised coagulopathy Ruptured abdominal aortic aneurysm Retroperitoneal haemorrhage Mediastinal haemorrhage Gastrointestinal haemorrhage

8 3 2 1 1 1

Sepsis multi-organ failure

59

Miscellaneous `Respiratory' aetiology Mesenteric ischaemia Pulmonary embolism Fulminant pancreatitis

22 10 8 3 1

Table 2. Peri-operative outcomes for synchronous CEA-CABG. Synchronous CEA ‡ CABG

Operative mortality

Ipsilateral stroke

Any stroke

Myocardial infarction

Death  ipsilat CVA

Death  any CVA

Death  any CVA  MI

Observed risk Risk % 95% CI Heterogeneity (p ˆ )

359/7753 4.6 4.1±5.2 0.0048

167/5643 3.0 2.4±3.5 0.0002

333/7206 4.6 3.9±5.4 50.0001

173/4800 3.6 3.0±4.2 0.0174

413/5563 7.4 6.5±8.3 0.0001

635/7260 8.7 7.7±9.8 50.0001

513/4463 11.5 10.1±12.9 50.000

Some papers did not provide all of this information and hence the denominator will not be the same as the total number of patients in the meta-analysis. n/a ˆ insufficient data to perform this analysis. Eur J Vasc Endovasc Surg Vol 26, September 2003

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Table 4. Peri-operative outcomes for patients undergoing synchronous CEA ‡ CABG relative to pre-operative neurological status. Operative mortality

Ipsilateral stroke

Any stroke

Myocardial infarction

Death  ipsilat CVA

Death  any CVA

Death  any CVA  MI

Asymptomatic Observed risk Risk % 95% CI Heterogeneity

33/925 3.6 2.1±5.0 0.1394

9/353 2.5 0.8±4.3 0.2675

48/1315 3.7 2.3±5.0 0.0160

2/89 2.2 0.0±4.8 0.5420

8/200 4.0 1.1±6.9 0.2761

36/799 4.5 2.6±6.4 0.0403

4/89 4.5 3.2±5.8 0.9672

Previous CVA/TIA Observed risk Risk % 95% CI Heterogeneity

30/514 5.8 4.2±7.5 0.7806

16/421 3.8 2.0±5.6 0.4303

61/892 6.8 4.6±9.1 0.0065

3/160 1.9 0.0±4.2 0.2576

11/194 5.7 2.5±8.8 0.4542

28/369 7.6 4.5±10.7 0.1518

13/160 8.1 4.0±12.3 0.4270

Some papers did not provide all of this information and hence the denominator will not be the same as the total number of patients in the meta-analysis. Table 5. Absolute risks and odds ratios derived from studies reporting outcomes for asymptomatic and symptomatic patients separately. No. of studies

Operative death Ipsilateral stroke Any stroke Death/ipsilat stroke Death/any stroke

10 11 16 6 8

Asymptomatic

Symptomatic

Difference

Observed

% (95% CI)

Observed

% (95% CI)

OR (95% CI)

Heterogeneity p

p

32/871 10/299 35/1088 7/97 35/696

3.7 (2.1±5.3) 3.2 (1.2±5.2) 3.2 (1.9±4.5) 7.4 (3.5±11.3) 5.1 (2.7±7.4)

23/395 15/311 43/624 4/84 20/259

5.9 (4.0±7.9) 4.7 (3.1±6.3) 6.8 (4.1±9.6) 5.2 (0.0±10.5) 7.9 (3.6±12.2)

1.5 (0.9±2.5) 1.3 (0.6±2.8) 1.8 (1.1±2.8) 0.9 (0.4±2.0) 1.6 (0.9±2.9)

0.9124 0.9391 0.5538 0.8128 0.8052

0.080 0.328 0.012 0.421 0.060

For example, 16 studies reported stroke rates for asymptomatic and symptomatic patients. It was, therefore, possible to calculate odds ratios for stroke risk within each study, and then combine these to produce a pooled estimate. The pooled estimate for the odds of any stroke indicated that symptomatic patients were 1.8 times more likely to suffer a stroke than asymptomatic patients. This difference was statistically significant (lower 95% CI of odds ratio 41.0, p ˆ 0.012). Importantly, there was also no significant heterogeneity (p 4 0.05) between the odds ratios derived from each of the individual studies, indicating that the trend towards a higher stroke risk in symptomatic patients was consistent across the studies and that pooled odds ratio was a valid summary estimate. (‡) Compares symptomatic against asymptomatic patients for each outcome.

indicates that each of the studies were reporting similar trends. Symptomatic patients were, however, significantly more likely to suffer an operative stroke than neurologically asymptomatic patients (odds ratio 1.8 (95% CI 1.1±2.8), p ˆ 0.012). Unilateral vs. bilateral carotid disease? Forty-eight series (2305 patients) published outcomes according to whether the patient had unilateral or bilateral carotid disease (Table 6). Unilateral carotid disease was defined as a 50±99% stenosis with either a normal contralateral carotid artery or a stenosis 550%. In practice, most had a 70±99% ipsilateral stenosis. Bilateral carotid disease was defined as a 50±99% stenosis in conjunction with a 50±99% stenosis or occlusion in the contralateral ICA. Overall, patients with bilateral carotid disease undergoing synchronous CEA ‡ CABG fared generally worse than patients with unilateral disease although no statistical comparisons could be made from the data in Table 6. Table 7 presents the observed risks, odds ratios and heterogeneity from studies reporting outcomes for

synchronous operations on patients with unilateral and bilateral disease. As was noted previously, the risks remain very similar to those presented in Table 6 (entire series). Overall, patients with bilateral disease were significantly more likely to suffer operative death (OR 2.0 (95% CI 1.1±3.3) p ˆ 0.05), any stroke (OR 1.7 (95% CI 1.0±2.5) p ˆ 0.048) or death/any stroke (OR 2.5 (95% CI 1.4±5.0) p ˆ 0.004). Although there was no statistically significant difference in the risk of ipsilateral stroke (3.9% vs. 3.4%, OR 1.1 (95% CI 0.5±2.0), p ˆ 0.98), the 95% confidence interval overlapped and closely corresponded with the estimates of increased risk of the other outcomes and was not statistically inconsistent. Synchronous CABG ‡ bilateral CEA Fifteen series6,23,25,32,35,37,41,45,53,69,77,78,84,93,99 reported that synchronous CABG and bilateral CEA had been performed in 151 patients. No specific outcome data was provided in five studies32,45,53,77,78 involving 67 patients and no operative mortality data was presented in a series of 16 patients by Vermeulen.99 Eur J Vasc Endovasc Surg Vol 26, September 2003

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Table 6. Peri-operative outcomes for patients undergoing synchronous CEA ‡ CABG relative to unilateral or bilateral carotid stenosis/ occlusion.

Unilateral 50±99% Observed risk Risk % 95% CI Heterogeneity

Operative mortality

Ipsilateral stroke

Any stroke

Myocardial infarction

Death  ipsilat CVA

Death  any CVA

Death  any CVA  MI

32/1017 3.1 2.0±4.3 0.2409

14/477 2.9 1.7±4.2 0.8229

54/1481 3.6 2.6±4.7 0.2122

6/246 2.2 0.6±4.2 0.5236

10/229 4.8 1.1±7.6 0.0700

71/784 4.0 2.2±5.7 0.0494

12/246 4.9 1.7±8.1 0.1564

18/519 3.5 2.2±4.8 0.8156

56/824 6.8 4.2±9.4 0.0002

1/96 1.0 0.0±3.8 0.0988

22/224 9.8 5.2±14.5 0.0856

36/324 11.1 5.2±17.0 0.0000

6/94 6.4 4.0±8.7 0.8776

Bilateral 50±99% or OCCLN Observed risk 29/419 Risk % 6.9 95% CI 3.9±9.9 Heterogeneity 0.0438

Some papers did not provide all of this information and hence the denominator will not be the same as the total number of patients in the meta-analysis. n/a ˆ insufficient data to perform this analysis. Table 7. Absolute risks and odds ratios derived from studies reporting outcomes for patients with unilateral and bilateral carotid disease separately. No. of studies

Operative death Ipsilateral stroke Any stroke Death/ipsilat stroke Death/any stroke

14 13 19 9 11

Unilateral

Bilateral

Difference

p

Observed

% (95% CI)

Observed

% (95% CI)

OR (95% CI)

Heterogeneity p

27/873 14/404 52/1337 8/156 25/640

3.1 (2.0±4.0) 3.4 (2.1±4.8) 3.9 (2.7±5.1) 4.9 (1.3±8.6) 3.9 (2.0±5.7)

25/355 13/321 47/645 17/141 30/260

6.9 (3.7±10.2) 3.9 (2.4±5.5) 7.2 (5.1±9.4) 12.3 (6.5±18.1) 11.7 (5.4±18.0)

2.0 (1.1±3.3) 1.1 (0.5±2.0) 1.7 (1.0±2.5) 3.2 (1.1±9.1) 2.5 (1.4±5.0)

0.9938 0.9755 0.6219 0.8691 0.9226

0.002 0.410 0.015 0.015 0.001

For example, 11 studies reported the risk of death/any stroke in patients with unilateral and bilateral carotid diseases separately. It was, therefore, possible to calculate odds ratios for stroke risk within each study, and then combine these to produce a pooled estimate. The pooled estimate for the odds of death/any stroke indicated that patients with bilateral carotid disease were 2.5 times more likely to suffer a death/any stroke than patients with unilateral disease. This difference was statistically significant (lower 95% CI of odds ratio 41.0, p ˆ 0.001). Importantly, there was also no significant heterogeneity (p 4 0.05) between the odds ratios derived from each of the individual studies, indicating that the trend towards a higher risk in patients with bilateral disease was consistent across the studies and that pooled odds ratio was a valid summary estimate. ( ‡ ) Compares patients with bilateral carotid disease against those with unilateral carotid disease for each outcome. Table 8. Peri-operative outcomes for patients undergoing synchronous CEA ‡ CABG relative to date of publication (1972±1992 vs. 1993±2002). Operative mortality

Ipsilateral stroke

Any stroke

Myocardial infarction

Death  ipsilat CVA

Death  any CVA

Death  any CVA  MI

1972±1992 Observed risk Risk % 95% CI Heterogeneity

123/2375 5.2 4.2±6.1 0.1896

78/1821 4.3 3.3±5.4 0.0719

160/2472 6.5 5.2±7.8 0.0008

80/1851 4.3 3.3±5.4 0.1437

158/1741 9.1 7.4±10.7 0.0211

253/2362 10.7 8.9±12.5 0.0001

248/1797 13.8 11.6±16.0 0.0016

1993±2002 Observed risk Risk % 95% CI Heterogeneity

236/5378 4.4 3.7±5.1 0.0066

58/4230 2.1 1.8±2.8 0.0766

171/5142 3.3 2.8±4.5 0.0000

92/2689 3.4 2.4±3.8 0.0940

255/4230 6.0 5.7±7.6 0.0163

382/5306 7.2 6.5±9.1 0.0000

265/3074 8.6 8.3±11.5 0.0005

Some papers did not provide all of this information and hence, the denominator will not be the same as the total number of patients in the meta-analysis.

Overall, the available published operative mortality rate was 2/68 (2.9%), while the operative stroke risk was 3/84 (3.6%). The death/any stroke rate following 68 CABG ‡ bilateral CEA procedures was a very low 2.9%. Eur J Vasc Endovasc Surg Vol 26, September 2003

Year of publication Forty-four series (2485 patients) were published between 1972±1992 inclusive, while 50 studies (5378 patients) were published between 1993±2002. Table 8

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Table 9. Peri-operative outcomes for patients undergoing synchronous CEA ‡ CABG relative to volume of procedures. Operative mortality

Ipsilateral stroke

Any stroke

Myocardial infarction

Death  ipsilat CVA

Death  any CVA

Death  any CVA  MI

550 Cases reported Observed risk Risk % (95% CI) 96% CI Heterogeneity

39/894 4.4 3.2±5.6 0.7706

24/745 3.2 2.0±4.4 0.5233

51/881 5.8 4.1±7.4 0.1501

14/643 2.2 1.2±3.1 0.8297

57/775 7.4 5.6±9.1 0.5243

85/881 9.6 7.5±11.8 0.1000

72/686 10.5 7.8±13.2 0.0436

50±99 Cases reported Observed risk Risk % (95% CI) 95% CI Heterogeneity

96/1799 5.3 3.9±6.8 0.0019

36/1338 2.7 1.3±4.1 0.0000

77/1799 4.3 2.5±6.0 0.0000

46/1446 3.2 2.0±4.4 0.0163

106/1338 7.9 5.4±10.5 0.0000

157/1727 9.1 6.4±11.8 0.0000

143/1318 10.8 7.8±13.9 0.0000

 100 Cases reported Observed risk Risk % (95% CI) 95% CI Heterogeneity

210/4760 4.4 3.6±5.2 0.0113

103/3360 3.1 2.2±3.9 0.0037

194/4226 4.6 3.5±5.7 0.0000

106/2511 4.2 2.9±5.5 0.0011

235/3250 7.2 6.1±8.4 0.0703

370/4352 8.5 6.9±10.1 0.0000

276/2259 12.2 10.0±14.5 0.0018

Some papers did not provide all of this information and hence, the denominator will not be the same as the total number of patients in the meta-analysis.

suggests that there has been an overall decrease in the risk of suffering any end-point in the more recently published series. In particular, the risk of death/ stroke/MI fell significantly from 13.8% (95% CI 11.6± 16.0) in studies published between 1972±1992 to 8.6% (95% CI 8.3±11.5) for studies published between 1993± 2002 (p ˆ 0.03). Number of reported cases Table 9 presents outcomes relative to the number of cases reported in the study. The aim of this particular analysis was to see whether `greater operative experience' was associated with better results. It was not possible to evaluate the effect of individual surgeon experience. Forty-three series (894 patients) described outcomes on studies containing 1±49 operated patients, 26 series (1799 patients) described outcomes on studies containing 50±99 patients, while 25 series (5170 patients) reported outcomes in studies containing 100 ‡ patients. As can be seen, there was no statistically significant difference in any end-point as the volume of surgical experience increased (p value for trend ˆ 0.64). Paradoxically, the highest overall cardiovascular risk for death/stroke/MI (12.2%, 95% CI 10.0±14.5) was observed in studies containing more than 100 patients. There was, however, considerable heterogeneity in the published risk relative to operative experience. Figure 1 presents the range of published risk of death/stroke relative to whether the paper reported 50±99 cases or 100 ‡ operations. As can be seen, the risk of death/any stroke varied from 1.2 to 28.3% in 25 studies reporting 50±99 cases as compared with 3.0±17.4% in 23 papers reporting outcomes on 4100 patients.

Timing of CEA relative to cardiopulmonary bypass There was considerable variation in practice regarding when CEA was performed relative to the patient going on to CPB. Table 9 details outcomes for fifty-nine studies (5496 patients) where CEA was performed before the patient went onto CPB, compared with 857 patients (16 studies) where CEA was performed after the patient had gone on to CPB. More recently, there has been a trend towards performing CEA first, followed by `CABG off-bypass'. The systematic review identified three studies (99 patients) in whom CABG had been performed off-bypass. It was not possible to perform statistical analyses on the three subgroups. However, broadly similar outcomes were observed irrespective of whether CEA was performed pre- or on bypass, particularly regarding the risk of death  any stroke (8% in both groups). However, the lowest complication rates were observed in the small series of patients undergoing CEA followed by CABG `off-bypass' (death/stroke/ MI risk ˆ 2.0%). Discussion This is the third in a series of systematic reviews dealing with the management of patients with cardiac and carotid artery disease. The first evaluated the risk of stroke following CABG with particular regard to the role of carotid artery disease in its pathogenesis.115 The second compared outcomes following staged and synchronous procedures.1,115 The principal conclusions from the first systematic review were that stroke complicates about 2.0% of all CABGs; with the Eur J Vasc Endovasc Surg Vol 26, September 2003

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Fig. 1. Heterogeneity of risk of death  any stroke following synchronous CEA-CABG relative to number of cases reported (50±99, 100 ‡ ). Eur J Vasc Endovasc Surg Vol 26, September 2003

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majority (62%) occurring after more than 24 h have elapsed. Secondly, although three `carotid' factors were significantly predictive of an increased risk of stroke after CABG (carotid bruit, previous TIA/ stroke, severe carotid artery stenosis/occlusion), approximately 50% of stroke sufferers did not have any evidence of significant carotid disease and up to 60% did not have territorial infarctions on autopsy/ CT that correlated with patterns of carotid disease. Thirdly, although the risk of post-CABG stroke increased with the severity and bilateral nature of any carotid disease (1.8% stroke risk in patients with no carotid disease, 3.2% in patients with unilateral 50± 99% stenoses, 5.2% in patients with bilateral 50±99% stenoses), the highest risk was observed in patients with carotid occlusion (7±12%) in whom staged and synchronous surgery would never be considered. In the second review, mortality was highest in patients undergoing synchronous CEA ‡ CABG (4.6%, 95% CI 4.1±5.2), while reverse staged procedures (CABG-CEA) were associated with the highest risk of stroke (6.3%, 95% CI 1.0±11.7). Peri-operative MI was lowest following reverse staged procedures (0.9%, 95% CI 0.5±1.4) and highest in patients undergoing staged CEA-CABG (6.5%, 95% CI 3.2±9.7). If, however, the analyses were limited only to those papers reporting outcomes for staged and synchronous procedures, there was no statistically significant difference in any of the outcomes. However, about 10± 12% of patients undergoing either staged or synchronous procedures died, or suffered a non-fatal stroke or MI. Unfortunately, there is no comparable data for patients with carotid disease undergoing CABG (without CEA). However, Das et al, have observed that (depending upon criteria used) the risk of death/ stroke may be as high as 8±12%.116 The aim of the current study was to analyse specified subgroups of patients undergoing synchronous CEA ‡ CABG in order to identify patterns of risk. Similar analyses were not possible following staged operations because of the relatively small number of papers documenting outcome as compared with synchronous operations. Overall, the worst outcomes (especially death/any stroke) were observed in patients with bilateral carotid disease (Tables 6 and 7). Interestingly, although symptomatic patients were significantly more likely to suffer an operative stroke, no other excess risk was observed regarding ipsilateral stroke, death and death/any stroke compared with asymptomatic patients. There does appear to have been a decline in risks in more recently published series (Table 8). Few studies have documented outcomes following bilateral CEA and CABG. The extremely good results

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identified in this review presumably reflect patient selection. Of practical importance was the observation that not one of these series reported any bilateral cranial nerve injuries. There were, however, three interesting observations arising from this review. Firstly, `operative experience' did not appear to be associated with outcome (Table 9). The risk of death/stroke was 9.6% (95% CI 7.5±11.8) in studies reporting 1±49 cases, as compared with 9.1% (95% CI 6.4±11.8) in studies containing 50±99 patients and 8.5% (6.9±10.1) in papers documenting outcome in 100 ‡ patients. Near identical patterns of outcome were also observed for death/ipsilateral stroke. Second, within these groupings of `increasing experience', there was considerable heterogeneity in the reporting of outcomes. This is amply demonstrated in Figure 1 (papers with 4100 patients) where there was a near six-fold increase in the risk of operative death/stroke from 3.0%48 to 17.4%.88 The latter study is of particular clinical relevance as it is one of the few contemporary, prospective, multicentre audits of outcome in the literature. In this study, all patients undergoing synchronous procedures in 10 states in the U.S.A. during a one-year period were prospectively audited.88 The 17.4% risk of operative death/stroke remains one of the highest documented in the literature, but might be more likely to represent `true' clinical practice. Finally, the timing of CEA with regard to CPB was of interest (Table 10) and merits closer scrutiny in the future. There was no apparent difference in any outcome when CEA was performed before or after going on to bypass. Conversely, the best results (1.0% death/ stroke) were observed in centres where CEA was performed first and then CABG undertaken `off-bypass' without any aortic cross-clamping. Unfortunately, only three studies (99 patients) have documented outcome using the latter operative strategy.75,85,93 There are clearly merits and disadvantages in performing off-bypass surgery and it is hoped that further data will be forthcoming in the future. The rationale for performing CABG `off-bypass' is based on recognition that aortic arch athero-thromboembolism is probably one of the most important causes of post-CABG stroke. This is based on observations that the risks of post-CABG stroke correlate closely with the presence of increasingly severe aortic atheroma. Patients with severe aortic arch disease (aortic wall thickening 45 mm, plus, either marked calcification or protruding/mobile atheroma or ulcerated plaque with overlying thrombus or circumferential involvement) have a 5±19% risk of peri-operative stroke as compared with 0±2% in patients with no significant aortic arch disease.117±120 More importantly, patients with a Eur J Vasc Endovasc Surg Vol 26, September 2003

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Table 10. Peri-operative outcomes for patients undergoing synchronous CEA + CABG relative to timing and mode of bypass. Operative mortality

Ipsilateral stroke

Any stroke

Myocardial infarction

Death  ipsilat CVA

Death  any CVA

Death  any CVA  MI

CEA pre-bypass Observed risk Risk % 95% CI Heterogeneity

245/5386 4.5 3.9±5.2 0.1469

126/4310 2.9 2.3±3.6 0.0042

247/5496 4.5 3.7±5.3 0.0000

133/3685 3.6 2.8±4.4 0.0011

307/4189 7.3 6.4±8.2 0.0423

442/5386 8.2 7.1±9.3 0.0000

395/3426 11.5 10.1±13.1 0.0006

CEA on bypass Observed risk Risk % 95% CI Heterogeneity

40/844 4.7 3.1±6.4 0.1802

17/807 2.1 1.4±2.8 0.9451

32/844 3.8 2.0±5.5 0.5016

8/273 2.9 1.3±4.6 0.7328

52/807 6.4 4.7±8.2 0.3732

68/844 8.1 5.8±10.3 0.0770

26/273 9.5 5.9±13.1 0.3399

1/99 1.0

1/99 1.0

1/99 1.0

1/99 1.0

1/99 1.0

2/99 2.0

CEA ‡ CABG off-bypass Observed risk 0/99 Risk % 0.0

Some papers did not provide all of this information and hence, the denominator will not be the same as the total number of patients in the meta-analysis.

combination of significant carotid and aortic arch disease appear to have a very high risk of stroke (14%) as compared to those with no evidence of aortic or carotid disease (0.9%).121 In conclusion, synchronous CEA ‡ CABG was associated with a not insignificant cardiovascular risk. Even within highly experienced centres, there was a six-fold variation in the risk of operative stroke/death. In a previous systematic review, Das observed that the risk of death/stroke varied from 8 to 12% (depending upon criteria) in patients with combined cardiac and coronary artery disease not subjected to staged or synchronous CEA.116 Future studies must clearly document these risks especially regarding demographic factors such as age, sex, neurological status and pattern of carotid disease. In the absence of randomised trial data, surgeons advocating synchronous (or staged) procedures must maintain a prospective audit of outcome.

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Eur J Vasc Endovasc Surg Vol 26, September 2003