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Three Part Question

In [patients undergoing cardiac surgery] does [asymptomatic significant carotid artery stenosis] reduce the long term incidence of [stroke].

Clinical Scenario

You see a patient on the coronary care unit referred for urgent CABG following angiographically demonstrated triple vessel disease including a significant left main stem lesion. On examination he is found to have a right sided carotid bruit. He is asymptomatic, having had no cerebrovascular accidents (CVAs) or transient ischaemic accidents (TIAs) in the past. He is on an anti-platelet agent.
On carotid Doppler examination he is found to have a 70% stenosis of the internal carotid artery on the right side. You wonder whether he would benefit from synchronous or staged CEA at the same time as CABG but you decide to search for the evidence for this prior to consulting a vascular surgeon.

Search Strategy

Medline 1966-Feb 2005 using OVID interface
[exp thoracic surgery/OR cardiac surgery.mp OR exp cardiac surgical procedures/OR exp coronary artery bypass/OR CABG.mp] AND [exp carotid stenosis/OR carotid stenosis.mp /OR carotid artery stenosis.mp] AND [exp endarterectomy, carotid/OR carotid endarterectomy.mp OR CEA.mp] LIMIT to human studies. In addition, the AHA guidelines and NICE guidelines were hand searched.

Search Outcome

Two hundred and ten papers were found of which 10 were deemed to be relevant. These papers are presented in the table

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Naylor et al, 2003, UK	Systematic review of 97 published studies following 8972 staged or synchronous CEA and CABG operations	Systematic review (level 2b)	Risk of stroke	Synchronous CEA and CABG 333/7206 (4.6%). Staged CEA then CABG 25/917 (2.7%). Staged CABG then CEA 19/302 (6.3%)	Without randomisation or standardisation between groups it is difficult to interpret with regard to symptomatology (60% of patients were asymptomatic). It does, however, review the real world outcome of these procedures whether for symptomatic or ASCAS.
			Operative mortality	Synchronous CEA and CABG 359/7753 (4.6%). Staged CEA then CABG 36/917 (3.9%). Staged CABG then CEA 6/302 (2.0%)
Gaudino et al, 2001, Italy	139 patients with severe (>80%) asymptomatic carotid artery stenosis undergoing CABG at a single centre Follow up to 5 years 73 had CABG alone, then there was a change in institutional policy and 66 had synchronous or staged CEA	Cohort study (level 3b)	Peri-operative CVA	CABG alone group 1/73. CABG and CEA 1/66 p=NS	Non-randomised study
			CVA or TIA after 5 years of follow up	CABG alone group 17/70. CABG and CEA 1/64 P<0.0001
Executive Committee for the Asymptomatic Carotid Atherosclerosis Study (ACAS), 1995, USA	1662 patients from 39 sites in USA and Canada between 1987 and 1993, with asymptomatic carotid artery stenosis of 60%-99% reduction in diameter were randomised to surgery plus medical therapy (n=828) or to medical therapy without carotid endarterectomey (n=834) All patient received aspirin (325 mg/d) with risk factor reduction counseling Follow-up data were available on 1659 patients	Multicentre PRCT (level 1b)	5 years risk of stroke	Surgical group 5.1%. Medical treatment 11.0%. Absolute risk reduction 5.9% P=0.004. There was no relationship between benefit and the degree of carotid artery stenosis	The ACAS investigators used the North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group stenosis criteria i.e. disease free distal internal carotid artery as denominator for the stenosis calculation, but the ECST stenosis definition is based on estimated normal lumen diameter at the site of the lesion. Thus a 60% ACAS stenosis corresponds with 76% to 80% diameter reduction by the ECST method
Chambers et al, 2004, UK	Systematic review up to 1997 performed, to investigate the role of carotid endarterectomy in preventing stroke in patients with asymptomatic carotid stenosis and to determine the effects of CEA for patients with asymptomatic carotid stenosis 6 completed randomised controlled trials comparing CEA to medical treatment in patients with asymptomatic carotid stenosis were identified but 2 were excluded on methodological grounds 4 trials with 2203 patients were included in the primary analysis	Systematic review (level 1a)	Any stroke or perioperative death	Surgical management 8.1%. Medical management 10.4%. Relative risk reduction 0.79 (95% CI:0.60-1.02, P=0.07)	Approximately one-third of those randomised in VA and ACAS had a history of contralateral symptoms or CEA It is possible that such patients are more at risk than those who have never had cerebrovascular symptoms 2 of the studies used for the primary analysis had less than 100 participants WRAMC and MACE, and compared CEA with aspirin This systematic review shows some evidence favouring CEA for asymptomatic carotid stenosis, the effect is at best barely significant statistically, and extremely small in terms of absolute risk reduction. Therefore extreme caution should be exercised in translating the results into clinical practice
			Perioperative stroke or death or subsequent ipsilateral stroke	Medical groups 6.8%. Surgical groups 4.9% in the surgical group with RR 0.73(95% CI:0.52-1.02, P=0.06) favouring surgery
			Rate of any stroke or death during perioperative or postoperative period	Medical groups 23.2%. Surgical groups 20.2% with RR 0.89 (95% CI:0.76-1.04, P=0.13)
European Carotid Surgery Collaborative Trialists Group.(ECST) 1998, UK	2295 patients from 100 centres in 14 countries recruited prior to January 1992 to investigate the risk of stroke in asymptomatic patients Stenoses measured by angiography This was a subset analysis of a larger PRCT investigating the treatment of symptomatic stenoses, with this study investigating the incidentally found stenoses on the contralateral side 4.5 year follow up	Cohort study (level 2b)	3 year risk of CVA	Asymptomatic stenosis of 30-69% 2.1%(1.1%-3.2%). Asymptomatic stenosis of 70-99% 5.7%(1.5%-9.8%). Asymptomatic occlusion 3.7%(0-8.9%)	The subjects of this study have had a symptomatic carotid event (even though this was in the territory of the carotid artery contralateral to that examined in this trial) and may well have different risk of stroke from those who have not had any clinical manifestation of carotid disease Study did not analyse the risk of transient ischaemic attacks during follow-up
Das et al, 2000, UK	Systematic review, searching MEDLINE, EMBASE and Cochrane upt ot 1999, looking for studies that investigate mortality and stroke rates for (1) unprotected CABG, (2) reverse stage procedures (CABG followed by CE, 3 months), (3) combined procedures (CABG + CEA) and (4) prior staged procedures (CEA followed by CABG, 3 months) Outcome was assessed by the 30-day permanent stroke and mortality rate for the different approaches	Systematic review (level 1a)	Accrued rates of permanent stroke and mortality rate expressed in terms of mean stroke and mortality rate (MSR, MMR)	Prior CEA followed by CABG, MSR 1.5%, MMR 5.9%. Unprotected CABG then CEA patients, MMR 3.8%, MMR 4.4%. CEA followed by CABG, MSR 2.4%, MMR 4.8%. Combined CABG and CEA at same operation, MSR 3.9%, MMR 4.5%. Comaprative analysis indicated a significant reduction in stroke for prior vs combined (1.5 vs 3.9%, P=0.007, odds 0.39, CI 0.2-0.77) with a higher mortality (5.9 vs 4.5%, P=0.1, odds 1.41, CI 0.96-2.06, NS). The stroke rate in the prior stage also remained significantly lower compared to the unprotected CABG group both for mixed (P=0.015) and asymptomatic CAS (P=0.047)	Data for each subcategory is obtained by summating the results of different trials with differing protocols and definitions of stroke, thus caution must be used when assessing these data of asymptomatic subgroups
Borger et al, 1999, Canada	Medline search of papers assessing CABG and CEA for symptomatic or asymptomatic carotid stenosis and CABG This meta-analysis only looked at whether staging the procedure was of benefit not whether it should be performed at all 16 studies reported and results combined	Meta-analysis (level 1b)	Incidence of stroke	Staged procedure 3.2%. Combined CEA and CABG 6.0% P=0.068
			Risk of death	Staged procedure 2.9%. Combined procedure 4.7% P=0.084
Biller et al, 1998, USA	Systematic review and expert panel consensus Patients with asymptomatic carotid artery disease	Systematic review (level 1a)	For patients with a surgical risk <3% and life expectancy of at least 5 years	Proven indications: Ipsilateral carotid endarterectomy is acceptable for stenotic lesions (>60% diameter reduction of distal outflow tract with or without ulceration and with or without antiplatelet therapy, irrespective of contralateral artery status, ranging from no disease occlusion (Grade A recommendation). Acceptable indications: Unilateral carotid endarterectomy simultaneous with coronary artery bypass graft for stenotic lesions (>60% with or without ulcerations with or without antiplatelet therapy irrespective of contralateral artery status (Grade C recommendation)
			For patients with a surgical risk of 3% to 5%	Prove indications: none. Acceptable but not proven indications: ipsilateral carotid endarterectomy for stenosis >75% with or without ulceration but in the presence of contralateral internal carotid artery stenosis ranging from 75% to total occlusion. Uncertain indications: ipsilateral carotid endarterectomy for stenosis >75% with or without ulceration irrespective of contralateral artery status ranging from no stenosis to occlusion. Coronary artery bypass graft required, with bilateral asymptomatic stenosis >70%, unilateral carotid endarterectomy with coronary artery bypass (CABG). Unilateral carotid stenosis >70%, CABG required, ipsilateral carotid endarterectomy with CABG.
			For patients with a surgical risk of 5% to 10%	Proven indications: None. Acceptable but not proven indications: None. Uncertain indications: Coronary bypass graft required with bilateral asymptomatic stenosis >70%, unilateral carotid endarterectomy with CAB. Unilateral carotid stenosis >70%, CABG required, ipsilateral carotid endarterectomy with CABG
AHA Guidelines, 2004, USA	Systematic review of the literature and expert consensus panel Note that full systematic review was not performed for our specific question concerning CEA and CABG	Systematic review (level 1a)	Recommendations for CEA and CABG	Carotid endarterectomy is probably recommended before CABG or concomitant to CABG in patients with a symptomatic carotid stenosis or in asymptomatic patients with unilateral or bilateral internal carotid stenosis of 80% or more (Level of Evidence:C). Asymptomatic stenois is not a reliabel protective correlate in these patients
			Recommendations for screening	Carotid screening is probably indicated in the following subsets: age greater than 65 years, left main coronary stenosis, peripheral vascular disease, history of smoking, history of transient ischemic attack or stroke, or carotid bruit on examination (Level of Evidence:C)
MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group, 1995, UK	3120 asymptomatic patients from 126 centres in 30 countries with substantial carotid artery stenois (60-99%) 1993-2003 were randomised equally, 1560 were allocated to immediate carotid endarterectomy and 1560 to indefinite deferral of any endarterectomy In the immediate CEA group, half got their operation within 1 month and 88% within 1 year In the deferred group only 4% per year went on to receive CEA after a neurological event Patients were followed for up to 5 years	Multicentre PRCT (level 1b)	Risk of stroke over 5 years (including perioperative stroke)	Risk of all strokes CEA group 6.4%. Non CEA group 11.8% net gain 5.4%(3.0-7.8), P<0.0001, 3.5% versus 6.1% for fatal or disabling strokes net gain 2.5%(0.8-4.3), P=0.004	All the patients in the symptomatic trials had their stenosis assessed by conventional angiography, suggesting that failure to detect the relevance of the stenosis in the asymptomatic trials might merely reflect imperfections of ultrasound as a sole technique of measurement The main analyses of the effects of surgery involved not only ipsilateral but also contralateral strokes Very well conducted trial
			Risk of peri-operative stroke	In CEA group the 30 day risk of stroke was 3.1% (95% CI 2.3-4.1) (5 year risk versus benefit balance was evident 2 years after CEA)

Comment(s)

There are several sources of papers that must be considered when addressing this difficult issue. Firstly, there are cohort studies looking at the results of various combinations of Carotid endarterectomy (CEA) and CABG or Coronary arterial bypass grafting without CEA. There are also several meta-analyses summarising these papers. Secondly, there are very strong multicentre trials that look at the issue of whether lone asymptomatic carotid stenosis without coronary disease mandates carotid endarterectomy. And thirdly, there are a number of guidelines that attempt to put these studies together to form a protocol for the treatment of Carotid stenosis in patients undergoing CABG. Of the meta-analyses of cohort studies that investigate CABG and CEA, Das et al summarised the published incidences of stroke and death for each strategy performed. CEA followed by CABG has a stroke rate of 1.5%, unprotected CABG then CEA had a stroke rate of 3.8%, CABG and CEA at the same operation had a stroke rate of 3.9%. Their findings that prior CEA then CABG is superior to alternative strategies was supported by the meta-analysis by Borger et al, who summarised 16 studies and concluded that CEA followed by CABG has a stroke rate of 3.2% compared to a combined approach that had a stroke rate of 6% (P=0.068). Naylor et al provided a further update on this issue in 2003 and again concluded that CEA prior to CABG was the safest treatment. These meta-analyses also provided breakdowns for asymptomatic patients and the findings were similar. A further weakness is that these meta-analyses did not report any cohorts of patients who had a significant stenosis but had a CABG alone (other than prior to delayed CEA). Gaudino et al. in 2001 reported 5 year follow up of a small cohort of 139 asymptomatic patients undergoing CABG alone compared to CEA and CABG. There was only one perioperative stroke in each group, but by 5 years 17 patients (24%) who did not have CEA had a stroke, compared to only one patient in the treatment group. We found no further studies such as this, however, with medium term follow up after these two strategies. The studies into lone asymptomatic carotid stenosis are, however, impressive. In 2004 the Asymptomatic Carotid Surgery Trial (ACST) reported their medium term results from 3120 patients randomised from 126 centres in 30 countries. They found that Carotid endarterectomy in asymptomatic stenosis led to a 5-year stroke rate of 6.4% compared to a stroke rate of 11.8% in patients randomised to the control group (P<0.0001). This study supported the findings of the Asymptomatic Carotid Atherosclerosis Study in 1995, that showed in a study of 1662 patients that those who had an endarterectomy had a 5-year incidence of stroke of 5% compared to 11% in the control group. These two RCTs contradicted a previous large cohort study by the European Carotid Surgery trialists collaborative who performed a sub-analysis of their RCT and found that those with an untreated carotid stenosis had only a 5.7% risk of stroke at 3 years and concluded that the benefit of surgical intervention would probably be contra-indicated. Finally, a Cochrane review in 2004 (Chambers) combined these two RCTs with 4 further RCTs to show a small benefit in favour of Carotid endarterectomy for asymptomatic stenosis. The third area of evidence is that of guidelines. The American Heart Association has provided two relevant guidelines in this area in 1998 and 2004. In 1998 the AHA provided guidelines for carotid endarterectomy. They concluded that in patients with an operative mortality of <3% and an expected life expectancy of more than 5 years requiring CABG with an asymptomatic carotid stenosis of more than 60%, carotid endarterectomy was not a proven indication but was an acceptable indication (based on grade C evidence). Patients with higher mortality may also have an acceptable indication if bilateral stenoses were present. This was also supported in the 2004 guidelines on coronary bypass grafting, where the AHA concluded that endarterectomy is 'probably' indicated in asymptomatic stenoses over 80% (based on grade C evidence). Therefore based on the above evidence, it is clear that lower risk patients with a significant asymptomatic carotid stenosis should be considered for carotid entarterectomy at some stage. When coronary arterial surgery is also required it is far less clear as to when the endarterectomy should be performed, and there is no strong evidence that this should be performed prior to, or during the coronary arterial bypass procedure.

Clinical Bottom Line

Low risk, younger patients with a significant asymptomatic carotid artery stenosis should be considered for carotid endarterectomy at some stage. There is, however, no strong evidence that this must be performed prior to, or during CABG.

References

1. Naylor R, Cuffe RL, Rothwell PM, Loftus IM, Bell PR. A systematic review of outcome following synchronous carotid endarterectomy and coronary artery bypass: influence of surgical and patient variables. Eur J Vasc Endovasc Surg 2003;26:230–241.
2. Gaudino M, Glieca F, Luciani N, Cellini C, Morelli M, Spatuzza P, Di Mauro M, Alessandrini F, Possati G. Should severe monolateral asymptomatic carotid artery stenosis be treated at the time of coronary artery bypass operation? Eur J Cardiothorac Surg 2001;19:619–626.
3. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study (ACAS). Endarterectomy for asymptomatic carotid artery stenosis. J Am Med Assoc 1995;273:1421–1428.
4. Chambers BR, You RX, Donnan GA. Carotid endarterectomy for asymptomatic carotid stenosis (Cochrane Review). The Cochrane Library 2004;Chichester, UK: John Wiley & Sons, Ltd. Art. No.: CD001923. DOI: 10.1002/14651858.CD001923
5. European Carotid Surgery Collaborative Trialists Group. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998;351:1379–1387.
6. Das SK, Brow TD, Pepper J. Continuing controversy in the management of concomitant coronary and carotid disease: an overview. Int J Cardiol 2000;74:47–65.
7. Borger MA, Fremes SE, Weisel RD, Cohen G, Rao V, Lindsay TF, Naylor CD. Coronary Bypass and Carotid Endarterectomy: Does a Combined Approach Increase Risk? A Metaanalysis. Ann Thorac Surg 1999;68:14–21.
8. Biller J, Feinberg WM, Castaldo JE, Whittemore AD, Harbaugh RE, Dempsey RJ, Caplan LR, Kresowik TF, Matchar DB, Toole JF, Easton JD, Adams HP. Guidelines for carotid endarterectomy: a statement for healthcare professionals from a special writing group of the stroke Council. American Heart Association Circulation Feb 1998;97:501–509.
9. Eagle KA, Guyton RA, Davidoff R, Edwards FH, Ewy GA, Gardner TJ, Hart JC, Herrmann HC, Hillis LD, Hutter AM Jr, Lytle BW, Marlow RA, Nugent WC, Orszulak TA. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery). American College of Cardiology Web Site.
10. MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. The European Carotid Surgery Trialists Collaborative Group. Risk of stroke in the distribution of an asymptomatic carotid artery. Lancet 1995;345:209–212.