Myocardial Revascularization with Carotid Artery Disease

	INTRODUCTION

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	PERIOPERATIVE STROKE

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Incidence of Perioperative Stroke

The risk of stroke coincident with CBG is well defined. In 1986, Gardner and colleagues¹ found the risk of stroke to be a direct function of patient age. Patients younger than 45 years of age had a stroke rate of 0.2%, which rose to 3.0% for patients in their 60s and to 8.0% for patients older than age 75. Other risk factors associated with stroke were preexisting cerebrovascular disease, ascending aortic atherosclerosis, long cardiopulmonary bypass time, and perioperative hypotension.

Tuman and colleagues² in 1992 investigated the effect of age on cardiac performance and neurologic injury in coronary bypass patients. Whereas the rates of low cardiac output and myocardial infarction (MI) were constant as patient age increased, the incidence of neurologic damage rose exponentially after age 65. The stroke rate rose from 0.9% for patients younger than 65 years to 8.9% for patients older than age 75.

To place the problem of the increasing age of coronary bypass patients into a more contemporary context, at our institution the mean age of coronary artery bypass (CAB) patients rose from 56 years in 1980 to over 68 years in 2001. In addition, in 1980 only 6% of patients were age 70 or older, whereas by 2001 over 45% were age 70 or older, and 13% were age 80 or older.

In 1995, John and colleagues³ reported a stroke rate of 1.4% for 19,224 coronary bypass patients from the New York State Cardiac Surgical Database. Multivariable predictors of stroke included aortic calcification, renal failure, prior stroke, smoking, carotid artery disease, age, peripheral vascular disease, and diabetes. In their review of 10,860 patients having primary myocardial revascularization, Puskas and colleagues⁴ noted that stroke occurred in 2.2%. Multivariable predictors of stroke were age, previous transient ischemic attack, and carotid bruits.

Cost of Perioperative Stroke

Puskas and colleagues⁴ also found that perioperative stroke was associated with significantly more in-hospital morbidity, longer length of stay, and almost twice the hospital cost. Patients who suffered a perioperative stroke had a 23% hospital mortality rate. Roach and colleagues⁵ noted a 21% mortality rate for patients suffering a perioperative stroke following coronary artery bypass grafting (CABG) with a mean hospital stay of 25 days among survivors.

Causes of Perioperative Stroke

Possible causes of perioperative neurologic injury are listed in Table 24-1. The most common cause of perioperative stroke is atherosclerotic or thrombotic emboli from the heart or major vessels. Intracardiac emboli can arise from mural thrombus secondary to MI, left atrial thrombus associated with valvular disease or atrial fibrillation, or suture lines in the aorta or left side of the heart. Catheters in the left side of the heart also can be a source of perioperative emboli. Less commonly, entrapped air may cause neurologic events, although rarely focal deficits.

Embolism from atherosclerotic carotid bifurcation disease is a well-defined cause of perioperative neurologic injury. Carotid plaque morphology has an important impact on the stroke risk of patients with carotid stenosis. A companion study to the North American Symptomatic Carotid Endarterectomy Trial found that plaque ulceration was a significant incremental risk factor for stroke across all degrees of carotid stenosis.⁷

Many studies list flow-limiting carotid stenosis as a risk factor for perioperative stroke, but whether the carotid lesion is an etiologic factor or only a nonspecific marker of overall risk is unclear.^1,8–10 The Buffalo Cardiac Cerebral Study Group found that while carotid stenosis predicted increased risk of perioperative stroke and death, most strokes occurred over 24 hours after the myocardial revascularization, and the anatomic distribution of the strokes did not correlate well with the site of the carotid lesion.^10,11

Neurologic injury can result from inadequate blood flow on cardiopulmonary bypass. Adequate perfusion pressure on bypass has been verified by Schwartz and colleagues,¹² who found that cerebral blood flow depends on arterial perfusion pressures, not on cardiopulmonary bypass flow rates. Low cerebral blood flow occurred with perfusion pressures of less than 60 mm Hg and was not influenced by the pump flow rate. Adequate perfusion pressure is very important in the presence of carotid stenosis, particularly with internal carotid occlusion.⁸ When there is occlusion of carotid or intracerebral arteries, brain blood flow depends on collateral circulation, which, in turn, depends on perfusion pressure. Whether carotid or intracerebral vascular spasm can contribute to neurologic injury is unknown.

Finally, intracranial hemorrhage can lead to neurologic injury following cardiopulmonary bypass, but the fact that this is truly rare is surprising, given that patients are fully anticoagulated for cardiopulmonary bypass. In our institution, where computed tomographic (CT) scanning is routine to evaluate suspected perioperative stroke to guide the use of heparin, the finding of primary intracerebral bleeding is extraordinarily uncommon.

Of all the potential causes of perioperative neurologic injury listed in Table 24-1, carotid stenosis is the one situation about which the surgeon routinely can take action to remove the pathology. Because carotid stenosis is a significant risk factor for perioperative stroke, the need to define carotid disease prior to coronary artery grafting becomes obvious. The logical extension that surgical correction of carotid stenosis can decrease the risk of stroke has been the basis of our approach, and that of others, for many years. While level I evidence to support this approach does not exist, the safety of the combined operative approach has been verified, as will be discussed.

Relationship of Carotid Stenosis to Perioperative Stroke

Early studies relating the presence of carotid stenosis to perioperative stroke used auscultatory evidence of carotid disease as a surrogate for carotid stenosis. In 1988, Reed and colleagues¹³ from our institution documented a 3.9-fold increase in the odds ratio for stroke in the presence of a carotid bruit.

Yet carotid bruits are reliable indicators of neither the presence nor degree of carotid stenosis. Sauve and colleagues¹⁴ found poor correlation between carotid bruits and the degree of carotid stenosis. Indeed, as carotid lesions progress to high degrees of stenosis, carotid bruits may become inaudible. Despite these limitations, auscultation for carotid bruits remains a common mode of detecting carotid stenosis, particularly in asymptomatic patients.

Currently, Doppler ultrasound–based noninvasive studies are the initially applied and often definitive (and sufficient) diagnostic testing modality for carotid stenosis. While quality control is essential with noninvasive testing, verification of its accuracy has been demonstrated many times.^15,16

Brener and colleagues⁸ studied 4047 cardiac surgical patients and found a 9.2% rate of stroke or transient ischemic attack in patients with asymptomatic carotid stenosis, significantly greater than the 1.3% rate in patients with no carotid stenosis.

Faggioli and colleagues¹⁷ in 1990 reported that routine carotid noninvasive testing in CAB patients with no ischemic neurologic symptoms yielded an odds ratio for stroke of 9.9 with greater than 75% carotid stenosis. In patients over age 60 with greater than 75% carotid stenosis, the stroke rate was 15 versus 0.6% for patients of the same age with no carotid disease. Perioperative strokes occurred in 4 (14.3%) of 28 patients who had greater than 75% carotid stenosis who did not have concomitant carotid endarterectomy compared with no strokes in the 19 patients with greater than 75% carotid stenosis who had a prophylactic carotid endarterectomy with their CABG.

In 1992, Berens and colleagues,¹⁸ using routine carotid duplex scanning for cardiac surgical patients 65 years of age or older, found that the risk of stroke was 2.5% for carotid stenoses greater than 50%, 7.6% for carotid stenoses greater than 50%, 10.9% for carotid stenoses greater than 80%, and 10.9% for unilateral carotid artery occlusion.

Thus, adequate evidence exists that significant carotid artery stenosis is an important incremental risk factor for the development of perioperative neurologic injury following CABG. In addition, the study by Faggioli and colleagues¹⁷ suggests that carotid endarterectomy performed with CABG yields a lower stroke rate.

Mechanism of Perioperative Stroke with Carotid Stenosis

How carotid stenoses cause perioperative strokes is not well understood, especially since patients are fully anticoagulated on cardiopulmonary bypass. Perioperative strokes may result from emboli from the carotid plaque possibly due to dynamic plaque events. Loss of pulsatile perfusion or an inadequate perfusion pressure on bypass may lead to diminished flow distal to a significant stenosis, resulting in a watershed stroke. However, Reed and colleagues¹³ and Ricotta and colleagues¹⁰ found that over one-half of strokes occur after the immediate postoperative period. Such delayed strokes in patients with uncorrected carotid stenoses may be related to the prothrombotic milieu that occurs in the early days after cardiopulmonary bypass, potentially causing destabilization of a previously asymptomatic carotid lesion.

Relationship of Uncorrected Carotid Stenosis to Late Stroke

In 1985, Barnes and colleagues¹⁹ assessed the late risk of untreated asymptomatic carotid stenosis in 65 patients who had cardiovascular operations, of whom 40 had CABG. At mean follow-up of only 22 months, 10% of coronary bypass patients had died, and 17.5% had suffered a stroke. Noninvasive testing revealed progression of the carotid artery disease in one-half the patients within 4 years. Contemporary randomized trials of surgery versus medical therapy for significant carotid stenosis have defined the late risk of carotid-related stroke in medically treated patients. In the landmark Asymptomatic Carotid Surgery Trial, actuarial risk of stroke at 5 years was 12% in medically treated patients.²⁰

	CAROTID STENOSIS IN CORONARY ARTERY BYPASS PATIENTS

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Incidence of Carotid Stenosis in Coronary Artery Bypass Patients

In 1977, Mehigan and colleagues,²¹ using noninvasive testing in 874 patients prior to coronary artery grafting, found a 6% incidence of significant extracranial cerebrovascular disease. Ivey and colleagues²² reported that routine ultrasonic duplex scanning for a history of neurologic events or cervical bruits in 1035 patients having isolated CABG revealed significant carotid artery stenosis in 86 patients (8.3%). Faggioli and colleagues¹⁷ evaluated 539 neurologically asymptomatic CAB patients using noninvasive methods and found that 8.7% had a carotid stenosis greater than 75%. The rate rose from 3.8% for patients younger than age 60 to 11.3% for patients over age 60. Berens and colleagues,¹⁸ using routine carotid artery scanning in 1087 candidates for cardiac surgery who were 65 years of age or older (91% with coronary disease), found that 186 (17.0%) had a greater than 50% carotid stenosis and that 65 (5.9%) had a greater than 80% carotid stenosis. Predictors of carotid artery disease were female gender, peripheral vascular disease, history of transient ischemic attacks (TIAs) or stroke, smoking history, and left main CAD. D’Agostino and colleagues,²³ using noninvasive carotid artery testing in 1279 CABG candidates, found that 262 (20.5%) had greater than 50% stenosis in at least one carotid artery and that 23 (1.8%) had bilateral stenoses greater than 80%. Significant multivariable predictors of carotid artery disease were age, diabetes, female sex, left main CAD, prior stroke, peripheral vascular disease, and smoking.

Diagnosis of Carotid Artery Disease

Physical examination

Palpation of a carotid artery provides little information about carotid stenosis, except for the correlation of a weak common carotid pulse with a very proximal flow-limiting stenosis, and theoretically can dislodge thrombus or embolic debris. As noted earlier, auscultation of carotid bruits cannot reveal the degree of carotid stenosis.

Essentials of noninvasive testing

Ultrasound-based Doppler interrogation for carotid stenosis exploits the Doppler effect; namely, the reflected or altered frequency of an ultrasound wave is shifted in proportion to the velocities of the sampled, flowing blood, which are increased in regions of significant arterial stenosis.

Current carotid noninvasive studies use several modalities combined into what is called triplex imaging. These include B-mode imaging to localize the bifurcation and characterize plaque morphology. Sophisticated high-resolution scanning is available for detailed plaque characterization, but this is largely an investigational tool and not a component of routine testing. Pulsed, ranged-gated Doppler is used to interrogate the common, internal, and external carotid arteries and establish the direction of vertebral artery flow in its cervical portion. Vertebral artery origins generally are obscured by bony structures. Doppler interrogation produces two data sets—first is Doppler-shifted flow velocities in regions of interest, and second is spectral analysis of turbulent flow, which lends a qualitative determination of stenosis severity. Doppler samples must be obtained in the tightest portion of the stenosis for accuracy.

Derived Doppler velocities include peak systolic velocity (PSV), end-diastolic velocity (EDV), and the ratio between the PSV in the internal carotid artery and in the proximal common carotid artery (ICA/CCA ratio). The derived ratio corrects for baseline variations in hemodynamics, such as cardiac output and increased overall flows, that might be noted in contralateral internal carotid occlusion. PSV is the single most important criterion, followed by the ICA/CCA ratio. EDV is helpful in discriminating severe versus "very severe" lesions. An ICA/CCA ratio of more than 4.0 equates to a greater than 70% diameter stenosis, the general threshold for a flow-reducing lesion at basal conditions according to the physics of critical arterial stenosis.

Supplementing direct Doppler interrogation are a number of indirect testing methods that can add additional information concerning the hemodynamic significance of the lesion and/or the status of intracranial collateral blood flow. Periorbital directional Doppler insonation of ophthalmic arteries and transcranial Doppler (TCD) are the principal indirect testing modalities; neither is applied routinely. Selective use, in particular of TCD, can provide helpful information on such variables as tandem lesions in the carotid siphon or middle cerebral stem, direction and adequacy of collateral flow through the circle of Willis, and intraprocedural monitoring.

Some general comments about the efficacy of ultrasound-based carotid noninvasive tests are in order because many vascular surgeons proceed to carotid endarterectomy based solely on these preoperative studies.¹⁶ Surgeons must be familiar with the specifics of noninvasive diagnostic criteria, and laboratories must have quality-control documentation of accuracy. Thorough knowledge of the translation of ultrasound-derived data to corresponding degrees of internal carotid artery stenosis is necessary. This is not a trivial consideration because the original Doppler velocity diagnostic criteria considered stenosis measurements at the carotid bulb (E method), whereas randomized trial data consider stenosis percentage referenced to the diameter of the normal distal internal carotid artery (N method).²⁴ While complete coverage of these important diagnostic caveats is beyond the scope of this chapter, comprehensive reviews are available.²⁵

Indications for noninvasive testing

Current indications for screening patients for carotid artery disease prior to surgical myocardial revascularization include

1. An audible bruit in the neck
   
2. History of a prior stroke
   
3. History of transient ischemic attacks
   
4. Patients with severe peripheral vascular disease
   
5. Patients with a prior carotid endarterectomy
   
6. Elderly patients
   

All of these indications are self-explanatory except the last. Because the incidence of carotid stenosis rises dramatically in patients over age 65, there must be an age at which it becomes cost-effective to screen all patients for carotid disease. However, that age limit has not yet been determined. One would have to demonstrate the cost advantage of routine carotid endarterectomy versus that of strokes related to uncorrected carotid stenoses.

Role of carotid angiographic modalities

CATHETER-BASED CAROTID ANGIOGRAPHY: At our institution until the mid-1990s, symptomatic patients with an audible bruit or asymptomatic patients with a noninvasive test suggesting severe carotid stenosis had catheter-based carotid angiography. While catheter-based carotid angiography yields excellent detailed images of the carotid and intracranial vessels, angiography is expensive, requires potentially nephrotoxic contrast material, and is not without risks, including arterial dissection and stroke. Cholesterol embolization owing to catheter manipulation in a diseased aorta can cause emboli to other vascular distributions, especially renal and/or other visceral arteries. (Indeed, in the Asymptomatic Carotid Atherosclerosis Study, one-half of the 2.3% stroke risk with carotid endarterectomy was referable to mandated angiography.²⁶) For these reasons, conventional carotid angiography had all but vanished from the practice of many vascular surgeons by the year 2000.²⁷ Ironically, current enthusiasm for carotid stenting has resurrected carotid angiography as a diagnostic and therapeutic tool.

MAGNETIC RESONANCE ANGIOGRAPHY: Great enthusiasm accompanied the introduction of magnetic resonance angiography (MRA) in the early 1990s to define carotid lesions because, compared with catheter-based angiography, it was noninvasive, lacked nephrotoxicity, and when used with diffusion-weighted brain imaging, yielded an extremely accurate map of the intracranial circulation. However, its limitations soon became obvious. These relate to the nature of the magnetic resonance vascular imaging, which relies on reflected magnetic pulses of flowing blood cells that vary as a function of flow turbulence. Since turbulent flow is characteristic of high-grade carotid stenoses, signal "dropout" in magnetic resonance imaging (MRI) is common. The literature verifies poor correlation of MRA with the precise degrees of stenosis. Indeed, MRA alone can overestimate carotid stenosis severity. Thus, in a reversal of prior algorithms, we insist that stenosis severity information from MRA be verified by a duplex study.

COMPUTED TOMOGRAPHIC ANGIOGRAPHY: Computed tomographic angiography (CTA) is the noninvasive test of choice when supplemental information is required after duplex scanning. While CTA requires iodinated contrast material, it can provide excellent arterial mapping from the aortic arch to the intracranial vasculature, which can be important to both vascular and cardiac surgeons. Accurate assessment of residual lumen diameter within a carotid artery lesion is obtained from both axial and three-dimensional (3-D) reconstructed images, with the important limitation that such accuracy diminishes in highly calcified lesions.

Definition of Severe Carotid Artery Stenosis

The definition of severe carotid stenosis has changed as techniques used to investigate carotid artery disease have changed. Severe carotid stenosis by direct carotid angiography reduces the residual lumen diameter to less than 1.5 mm or by more than 70%. With MRA, severe stenosis causes signal dropout. The definition of severe stenosis with ultrasound-based scanning was presented earlier.

	EFFICACY OF CAROTID ENDARTERECTOMY AS A TREATMENT FOR CAROTID STENOSIS

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C. Miller Fisher’s original description of the relationship of ipsilateral hemispheric stroke to internal carotid artery occlusion in 1951²⁸ was followed by Eastcott’s description of surgical therapy for symptomatic carotid artery atherosclerosis in 1953.²⁹ Thereafter, carotid endarterectomy became popular for stroke prevention until publication of the negative results in the multinational EC/IC bypass trial³⁰ in the mid-1980s. A vocal segment of the neurology community decried the apparent lack of evidence verifying the efficacy of carotid endarterectomy in stroke prevention, which led to a series of large-scale, prospective, randomized trials comparing carotid endarterectomy with medical therapy. In summary, there is now Level I evidence verifying the efficacy of carotid endarterectomy for stroke prevention in both symptomatic and asymptomatic patients.

Carotid Endarterectomy for Symptomatic Carotid Stenosis

In 1986, Hertzer and colleagues³¹ studied 211 patients with TIAs or strokes and a carotid stenosis greater than 50%, of whom 126 had medical treatment and 85 had carotid endarterectomy. Although there was no difference in survival between the two groups at a mean follow-up of 36 months, carotid endarterectomy yielded significantly better freedom from late stroke for patients with (1) a greater than 70% unilateral stenosis, (2) greater than 50% bilateral stenoses, and (3) a greater than 50% carotid stenosis in association with contralateral internal carotid artery occlusions. This study set the stage for several large-scale, randomized trials.

In 1991, the results of the randomized North American Symptomatic Carotid Endarterectomy Trial (NASCET) of medical treatment or carotid endarterectomy were reported.²⁴ All patients had either hemispheric retinal TIAs or nondisabling strokes within 120 days of entry into the trial and 70 to 99% stenosis in the symptomatic carotid artery. The actuarial risk of any ipsilateral stroke at 2 years was significantly lower at 9% in the 328 surgical patients versus 26% in the 331 medical patients. The data-safety monitoring committee halted further randomization given the widely disparate 18-month follow-up data. For major or fatal ipsilateral strokes, the risk was 2.5% for surgical patients versus 13.1% for medical patients (p <.001). When all strokes and deaths were included, carotid endarterectomy still was better than medical treatment. Subsequent follow-up studies from the NASCET investigators indicated that the benefit of carotid endarterectomy in symptomatic patients also extended to those with even moderate (50 to 69%) carotid artery lesions.³²

Also in 1991, the Veterans Affairs Cooperative Study of symptomatic carotid stenosis reported its results of randomization of 189 men with stenoses greater than 50% to medical or surgical treatment.³³ After 1 year, there was a significant reduction in stroke or TIAs in the patients having carotid endarterectomy (7.7%) compared with medically treated patients (19.4%). The results were even more divergent for patients with a carotid stenosis greater than 70%.

The European Carotid Surgery Trial randomized 2518 patients with nondisabling stroke, TIA, or retinal infarction in conjunction with stenosis in the ipsilateral carotid artery to medical or surgical treatment.³⁴ For the 778 patients with severe stenoses of 70 to 99%, the cumulative risk of stroke at carotid endarterectomy of 7.5%, plus an additional late stroke rate at 3 years of 2.8%, was less than the 16.8% rate for medically treated patients. At 3 years, the cumulative risk of operative death, operative stroke, ipsilateral ischemic stroke, and any other stroke was 12.3% for the surgical cohort versus 21.9% for the medical group (p <.01). Finally, the risk of fatal or disabling ipsilateral stroke at 3 years was 6.0% for the carotid endarterectomy patients versus 11.0% for the medical control patients (p <.05).

Although the benefit of carotid endarterectomy in these studies was due in part to the high risk of stroke in medically treated patients, the results were significant even in an era when the 30-day combined stroke and death risk of carotid endarterectomy was about 7.5%. While the combined stroke and death risk with carotid endarterectomy is higher in symptomatic versus asymptomatic patients, the current combined risk is closer to 3 to 5%.^20,27,35,36

Carotid Endarterectomy for Asymptomatic Carotid Stenosis

Hertzer’s group studied operative and nonoperative treatment in 290 previously unoperated patients who had greater than 50% asymptomatic carotid stenoses.³⁷ During follow-up to 3 years, prophylactic carotid endarterectomy in 95 patients had a significantly reduced incidence of neurologic events compared with medical treatment in 195 patients (p = .05).

Data from Moneta and colleagues³⁸ indicate that carotid endarterectomy patients had a significantly lower stroke risk compared with the natural history of patients without intervention. This study also suggested that late coronary events were so frequent as to question the wisdom of intervention for the carotid artery lesion. Accordingly, a series of trials in asymptomatic patients were performed.

The Veterans Affairs Cooperative Study of asymptomatic carotid stenosis, defined as greater than 50% diameter reduction by angiography, randomized 444 men to medical or surgical treatment.³⁹ At a mean follow-up of 4 years, the combined incidence of ipsilateral neurologic events was 8.0% for the surgical patients versus 20.6% for the medical patients (p < .001). The difference in stroke alone between the two groups (8 versus 20%) did not achieve statistical significance because of the study’s sample size, nor was there a significant difference when all strokes and deaths were analyzed. Excessive late mortality (about 40% at 4 years in both groups) was due largely to associated CAD. These mitigating factors limited definitive conclusions about the efficacy of carotid endarterectomy in asymptomatic patients in this trial.

In 1995, the results of the Asymptomatic Carotid Atherosclerosis Study of 1662 patients randomized to surgical or medical treatment were published.²⁶ At mean follow-up of 2.7 years, aggregate risk for ipsilateral stroke and any perioperative stroke or death for the surgical group was 5.1%, significantly lower than the rate of ipsilateral stroke of 11.0% for the medical group, a benefit limited to male patients. Critics suggested that the low combined stroke and death rate (2.3%) in the surgical patients was not representative of results across a broader spectrum of hospitals.

In 2004, the Asymptomatic Carotid Surgery Trial (ACST) contributed important data on the value of carotid endarterectomy for asymptomatic carotid stenosis.²⁰ Touted as the world’s largest surgical trial from 126 hospitals in over 30 countries, the study randomized over 3000 patients to carotid endarterectomy or medical therapy, which included at least aspirin. Over 40% of randomized patients had over 3 years of follow-up. Risk of any stroke, any ipsilateral stroke, or any disabling stroke was halved in surgical patients, who had a perioperative combined stroke and death rate of about 3%. The time threshold to achieve statistical benefit, i.e., cancel perioperative morbidity, by actuarial analysis was 2 years, suggesting that patients selected for endarterectomy should have a life expectancy of greater than 2 years. Indeed, the only subgroup in which endarterectomy did not achieve statistical significance was in patients over 75 years of age.

In summary, Level I evidence supports the advantage of carotid endarterectomy over medical management for patients with severe asymptomatic carotid artery stenoses.

	CAROTID STENTING

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Following the success of percutaneous transluminal coronary angioplasty, particularly with adjunctive stenting, percutaneous interventionalists increasingly sought to treat carotid stenosis with angioplasty and stenting.^40–42 Technical aspects of the procedure to guard against procedure-related stroke dominated the first years of its evolution. Today, use of distal embolic protection devices potentially makes carotid stenting comparable with carotid endarterectomy in safety and efficacy.⁴³ Emerging reports (mostly from industry-sponsored trials) indicate that carotid stenting can produce equivalent outcomes to carotid endarterectomy.^44–47 In one large series, the 30-day combined stroke and death rate was 7.4%, and most strokes were minor.⁴⁸ Results improved with experience, and late stroke-free survival was comparable with that for carotid endarterectomy.

In 2004, the initial randomized trial of carotid endarterectomy versus stenting with routine embolic protection, designed as a "noninferiority" trial, i.e., insufficiently powered to detect superiority of one treatment, concluded that carotid stenting was not inferior to carotid endarterectomy in high-risk patients.⁴⁷ Study endpoints (composite death/stroke/MI at 30 days and 1 year) and the high 30-day combined stroke and death rate (5.7%) in asymptomatic patients limit the value of the data. While a number of trials of carotid stenting versus carotid endarterectomy in various patient subsets are underway, the recently published French carotid endarterectomy versus stenting study in patients with symptomatic, severe carotid stenosis indicated that stenting is associated with a 2.2-fold increased risk of stroke or death at 30 days compared with endarterectomy. The trial was halted by the data-safety monitoring committee after the randomization of 527 patients.⁴⁹ Furthermore, published evidence documents an increased periprocedural risk of stroke after carotid stenting in elderly patients.⁵⁰

Scant data are available about carotid artery stenting versus endarterectomy in patients requiring CABG. Investigators from the Cleveland Clinic compared patients treated with either carotid artery stenting before or carotid endarterectomy with open-heart surgery. After propensity scoring, the authors found no significant differences in combined stroke/death/MI in the two approaches.⁵¹

	MYOCARDIAL ISCHEMIC EVENTS IN PATIENTS AFTER CAROTID ENDARTERECTOMY

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Although this chapter is focused primarily on managing CAB patients who have concomitant carotid artery disease, some comment on the impact of CAD on short- and long-term risks of carotid endarterectomy patients is appropriate.

Incidence of Coronary Artery Disease in Carotid Endarterectomy Patients

Mackey and colleagues⁵² found that 53% of carotid endarterectomy patients had evidence of CAD by clinical history or electrocardiographic studies. Using thallium exercise testing in 106 carotid endarterectomy patients, Urbinati and colleagues⁵³ found that 27 (25%) had significant defects on myocardial scanning. In 1985, the Cleveland Clinic reported the results of routine preoperative coronary angiography in 506 carotid endarterectomy patients.⁵⁴ Only 7% of patients had normal coronary arteries, and 28% had mild to moderate CAD. However, 30% had advanced but compensated disease, 28% had severe, correctable disease, and 7% had severe, inoperable CAD.

Risk of Myocardial Ischemic Events

Short-term risks

The impact of CAD on the short-term risks of carotid endarterectomy is well documented. In 1981, Hertzer and colleagues⁵⁵ reported that hospital mortality in 335 carotid endarterectomy patients was 1.8%, of which 60% of deaths were due to CAD. In the Mackey and colleagues study cited earlier, carotid endarterectomy patients with clinical CAD had an operative mortality of 1.5% and an MI rate of 4.3% compared with no mortality and an infarction rate of 0.5% for patients without CAD.⁵² While the frequent coexistence of CAD with carotid artery disease is often invoked as the principal cause of short- and long-term morbidity in carotid endarterectomy patients, the risk of perioperative MI will vary with the risk profile of the cohort studied. For example, in the protected carotid artery stenting versus endarterectomy trial, 30-day non-Q-wave MI occurred in 6.6%.⁴⁷ In our cohort of over 2000 carotid endarterectomy patients, the perioperative MI rate was 1.2%.²⁷ A National Surgical Quality Improvement Program (NSQIP) database report of over 13,000 endarterectomy procedures had a perioperative MI rate of 1.4%,⁵⁶ similar to results from the ACST trial.²⁰ Clearly, improved care has lowered coronary ischemic risks during carotid endarterectomy.

Long-term risks

Mackey’s study of carotid endarterectomy patients reported the 5- and 10-year survival rates of patients with CAD to be 68.6 and 44.9%, respectively, versus 86.4 and 72.3% for patients with no CAD.⁵² When Urbinati and colleagues⁵³ followed their carotid endarterectomy patients, the 7-year freedom from all cardiac events was 51% for patients with silent myocardial ischemia compared with 98% for patients with normal thallium exercise testing.

In the Hertzer and colleagues study⁵⁵ of 209 patients with clinically suspected CAD, 5-year mortality rate for hospital survivors was 27%, and 37% of late deaths were due to MI. Actuarial survival at 11 years was significantly better for the patients with CAD who had bypass grafting. A later study from the same group of 329 carotid endarterectomy patients followed to 10 years confirmed that MI caused more late deaths (37%) than did stroke (15%).⁵⁷ Again, 10-year survival was significantly better for patients having CABG.

In our Massachusetts General Hospital cohort of over 2000 carotid endarterectomy patients treated between 1990 and 1999, 10-year actuarial survival was 45%. Among variables associated with increased late mortality, concomitant CAD [odds ratio (OR) 1.4; p = .0002] figured prominently.²⁷

	TIMING OF CAROTID AND CORONARY ARTERY SURGERY

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If one accepts that (1) uncorrected carotid stenosis increases the risk of stroke for patients with severe carotid and CAD who have only isolated CABG, (2) carotid endarterectomy is the indicated treatment for severe symptomatic and asymptomatic carotid stenosis, (3) CAD increases the early and late risk of death for carotid endarterectomy patients, and (4) CABG is an indicated treatment for CAD, then the important question becomes not the indication for but the timing of the two operative procedures.

Staged Carotid and Coronary Artery Operations

One approach is to perform the carotid endarterectomy and CAB operations as staged procedures. By convention, doing the carotid endarterectomy before coronary bypass grafting is referred to as a staged procedure, whereas doing the CABG before the carotid artery operation is called a reverse staged procedure.

Most surgeons who advocate a sequential operative approach to patients with severe combined disease usually do the carotid endarterectomy first if the patient is not ischemic and is hemodynamically stable. Improvements in patient management, especially use of regional anesthesia, often can allow safe initial isolated carotid endarterectomy. Recent data from studies powered to detect an impact of regional anesthesia have verified that composite outcomes of stroke/death/MI after carotid endarterectomy are reduced significantly with use of regional anesthesia.^56,58 However, other practical considerations, such as imminent need for the large doses of heparin required for cardiopulmonary bypass, airway and/or neck swelling, and the risk of perioperative coronary ischemic events, remain real issues.

For unstable cardiac patients, particularly those with asymptomatic carotid stenosis, some cardiac surgeons opt to perform initial myocardial revascularization followed by an interval carotid endarterectomy. The principal risk with this approach is the potential for neurologic complications either during or shortly after the myocardial revascularization.

Currently, we advocate concomitant carotid and coronary artery operations for virtually all patients with severe combined disease. However, in patients with severe bilateral carotid stenosis, a staged approach may be appropriate, especially if the patient is stable cardiovascularly. We occasionally treat the more severe of the two carotid artery lesions with initial isolated endarterectomy, followed by combined CABG and endarterectomy of the other carotid artery within a few days. Use of a reversed staged approach, namely, doing one carotid endarterectomy with myocardial revascularization followed several days later by the other carotid endarterectomy, is rare because of an increased stroke risk with reversed staged procedures (to be discussed below).

Concomitant Carotid and Coronary Artery Operations

In 1972, Bernhard and colleagues⁵⁹ published the first report of successful combined carotid endarterectomy and CABG in 15 patients. Since then, numerous groups have published their results. The strategy of performing both operative procedures during one anesthetic is based on the premise that such an approach in patients with severe combined disease ought to minimize cardiac events that frequently complicate isolated carotid endarterectomy and neurologic events that complicate isolated CABG.

Daily and colleagues⁶⁰ reported that doing both operative procedures together is more cost-effective than a staged or reversed staged approach, which require two anesthetics and can incur the additional costs of two hospitalizations.

	OPERATIVE TECHNIQUES FOR CONCOMITANT CAROTID AND CORONARY ARTERY OPERATIONS

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Standard Approach

The usual operative technique for concomitant carotid endarterectomy and CABG has been to perform the carotid endarterectomy during harvesting of CAD conduits prior to cardiopulmonary bypass, the approach we use at our institution, where the carotid operation is performed by vascular surgeons as the cardiac surgical team harvests whatever saphenous vein or other conduits may be needed.

Technical components of carotid endarterectomy have evolved over time. Preoperative aspirin has been validated in large database studies.⁶¹ We use routine electroencephalographic monitoring, selective shunting, and either eversion endarterectomy (presuming no need for a shunt) or patch closure. Simple primary closure is associated with a higher rate of restenosis.⁶² After the carotid endarterectomy is completed, the neck incision is loosely approximated over a sponge. Final closure, usually over a plastic drain, is done after cardiopulmonary bypass is completed and heparinization is reversed.

Alternative Approaches

Minami and colleagues⁶³ reported using some perceived advantages of cardiopulmonary bypass, namely, heparinization, hypothermia, and hemodynamic control, to perform carotid endarterectomy in 116 patients while on bypass for CABG. Operative mortality was 1.7%, and total stroke risk was 4.3%. Weiss and colleagues⁶⁴ perform the carotid endarterectomy on bypass with systemic hypothermia to 20°C with the heart protected with cardioplegia. They had no neurologic events and one postoperative death in 23 patients. Theoretically, hypothermia on cardiopulmonary bypass provides an extra margin of ischemic protection for the brain during the carotid endarterectomy and avoids the need for intravascular shunting. The level of systemic hypothermia used has varied among surgical groups employing this approach.

Whether performing the carotid and coronary artery operations on cardiopulmonary bypass saves total operative time is not proven, but it prolongs aortic occlusion and cardiopulmonary bypass times, something most cardiac surgeons would prefer to avoid. A deeper level of hypothermia is not favored by most cardiac surgeons, particularly as the trend toward using lesser degrees of hypothermia has become more popular.

	HIGHLIGHTS OF POSTOPERATIVE MANAGEMENT

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In our institution, postoperative management of patients following concomitant carotid endarterectomy and CABG does not differ importantly from the management of patients having isolated myocardial revascularization. We believe that maintenance of a good coronary perfusion pressure and, by extension, good cerebral perfusion pressure in the early postoperative hours is beneficial. Early clearing of perioperative edema with diuresis seems to be efficacious.

The routine anticoagulation protocol for our myocardial revascularization patients, aspirin begun within 6 hours of completion of the operation, is adequate for patients who have either primary or saphenous vein patch closure of the carotid arterotomy. When a prosthetic patch is used, the patient has considerable residual disease higher in the carotid system, or contralateral carotid disease is uncorrected, especially if the plaque is ulcerated, some surgeons prefer early anticoagulation with heparin, followed by long-term warfarin anticoagulation.

If a surgeon decides not to treat a severe carotid stenosis either with a staged approach or concomitant operation, the increased incidence of stroke in the early days after isolated myocardial revascularization seen with the reversed staged approach would seem to suggest that heparinization of the patient is appropriate once the acute bleeding risk of the CAB operation is past.

	RESULTS OF STAGED AND CONCOMITANT CAROTID AND CORONARY ARTERY OPERATIONS

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Early Results

Staged carotid and coronary artery operations

Several studies report the results of staged operations for concomitant carotid and CAD, but only one study randomized patients to concomitant or reversed staged operation. Hertzer and colleagues⁶⁵ published a study containing a randomized subgroup of patients with unstable coronary artery syndromes and incidental asymptomatic carotid stenosis. Over 5 years, these authors treated 275 patients with severe combined disease. Their criteria for carotid endarterectomy was symptomatic and/or severe (>70%) carotid artery disease. Only 24 (9%) of the patients had CAD that was stable enough to allow carotid endarterectomy prior to CABG. Of those 24 patients, 1 (4.2%) suffered a perioperative stroke after the carotid endarterectomy and died of an MI awaiting CABG. Symptomatic or severe bilateral carotid artery disease in 122 patients was treated with combined carotid and coronary artery operation with an operative mortality rate of 6.1% and a perioperative stroke rate of 7.1%.

The remaining 129 patients with unstable coronary artery symptoms and unilateral, asymptomatic, severe carotid stenoses were randomized to either a combined operation or a reversed staged operation. Patients having concomitant carotid and coronary artery operations had a mortality rate of 4.2% versus a combined rate of 5.3% for the two operations in the staged patients. The incidence of stroke in the concomitant operations was 2.8%, which was significantly lower than the 14% risk of the reversed staged operations (6.9% during the isolated CABG and 7.5% during the delayed isolated carotid endarterectomy). This randomized study emphasizes the advantage of concomitant operations over reversed staged procedures.

In 1999, Borger and colleagues⁶⁶ performed a meta-analysis of nonrandomized observational studies published from centers that documented results with both staged and concomitant operations. They identified a trend toward increased risk of stroke and death with combined operations. The results of this study need to be viewed with caution for several reasons. First, using meta-analysis to compare observational and nonrandomized studies limits its statistical power. Second, in most series, unstable patients had combined operations and stable patients had staged procedures. Third, the criteria for entry into these studies was operations completed, not intention to treat. One cannot be sure if some patients for whom a staged approach was planned were not studied because the second operation was never performed due to a poor result from the first procedure.

Concomitant carotid and coronary artery operations

Since the late 1970s, some surgeons in our group have had an aggressive approach to patients with combined carotid and CAD, using concomitant operative repair as the standard approach. Staged operations were reserved for the few patients with very stable CAD. Our first report in 1989 in a small group of patients suggested that combined operation was safe (2% stroke or death risk). That study was among the first to document the disparate cardiac risk among patients having combined operations versus patients having isolated CABG.⁶⁷

In 1995 we published our results of combined operations between 1979 and 1993 in the first 200 consecutive patients.⁶⁸ Hospital mortality was 3.5%, MI 2.5%, and perioperative stroke 4.0%.

More recently, we published results of concomitant operation between 1979 and 2001 in 500 patients, with that approach being used in virtually all patients with combined disease since our second report.⁶⁹ Mean patient age was 69 years, about 6 years older than that for all CAB patients during that time period. Three-quarters of the patients had unstable angina pectoris, and 53% had prior MI. Although the distribution of single-, double-, and triple-vessel disease was as expected at 4%, 21%, and 75%, respectively, 42% of patients had significant left main CAD. Of the 500 patients, 329 (66%) were neurologically asymptomatic, 21% had transient ischemic attacks, and 13% had a prior stroke. Unilateral severe carotid stenosis was found in 336 patients (67%); 32% had disease in the contralateral carotid artery.

Urgent or emergency operations were required in 54% of patients; 3% were on the intra-aortic balloon preoperatively. The average number of grafts per patient was 3.7. While only 50% of the first 200 patients received at least one mammary artery graft, 90% of the last 300 patients received a mammary artery graft.

Hospital mortality was 3.6%, MI was 2.0%, and stroke occurred in 4.6%. Of the 23 strokes, 12 were ipsilateral to the carotid endarterectomy and 11 contralateral or bilateral, suggesting that, in our experience, concomitant carotid endarterectomy and CABG have neutralized the impact of carotid stenosis as a risk factor for stroke during surgical myocardial revascularization.

Significant multivariate predictors of hospital death were preoperative TIAs, preoperative MI, and nonelective operation. Peripheral vascular disease predicted postoperative stroke. Significant predictors of prolonged postoperative hospital stay were failure to use a mammary artery graft, perioperative stroke, and advanced age.

Vermeulen and colleagues⁷⁰ found that the only significant multivariate predictor of hospital death in 230 combined operations was left main CAD. Postoperative neurologic events were predicted by severe left ventricular dysfunction and preoperative neurologic events, either stroke or TIAs.

Several series of concomitant carotid endarterectomy and CABG published since 1985 are noted in Table 24-2. Our results stand in contrast to some others, particularly reports using administrative data. Brown reported a 17.7% stroke risk for combined operations in Medicare patients in Midwestern states.⁷¹ A Canadian study found that the combined risk of stroke and death for CABG alone was 4.9% versus 13% for combined carotid and coronary artery operations.⁷² However, data available from the New York State Registry indicate that such results can be explained largely by the disparate cardiac risk profiles of the two patient groups. Ricotta and colleagues⁹ used propensity scoring to match risk-factor profiling and found no difference in combined stroke and death risk for the two operations after case-control matching.

Follow-up in our series of combined operations revealed the following 10-year actuarial freedoms from late events: death, 43%; MI, 87%; percutaneous transluminal coronary angioplasty, 92%; reoperative myocardial revascularization, 96%; total stroke, 85%; and ipsilateral stroke, 90%.⁶⁹

Vermeulen and colleagues⁷⁰ found their 10-year actuarial freedom from cardiac events to be 50%, from neurologic events to be 81%, and from all events to be 41%. The only significant multivariate predictors of late cardiac mortality were advanced age and severe left ventricular dysfunction.

In a study of 127 combined carotid and coronary artery operations, Rizzo and colleagues⁷³ reported a 5-year survival rate of 70%, freedom from MI of 84%, and freedom from stroke of 88%. Survival was worse for patients with low ejection fractions. Late strokes were fewer in patients who were neurologically asymptomatic preoperatively, more common in patients who were transiently symptomatic, and most frequent in patients with prior stroke.

	CONCLUSION

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The risk of perioperative stroke following myocardial revascularization rises with the increasing age of CABG patients, and increasing age is accompanied by an increased incidence of carotid artery disease. Several studies have defined severe, uncorrected carotid stenosis as a major risk factor for perioperative stroke. Therefore, in addition to patients with audible carotid bruits or a history of ischemic neurologic events, patients who are 65 years of age or older ought to have noninvasive carotid artery evaluation prior to CABG. Also, randomized trials have established the safety and efficacy of carotid endarterectomy as the most appropriate treatment for both symptomatic and asymptomatic severe carotid stenosis. Another randomized study has demonstrated the advantage of concomitant carotid endarterectomy and CABG over reversed staged operations. Thus, we advocate combined carotid and coronary artery operations for virtually all patients with severe concomitant coronary and carotid artery disease, which on its own merits would require treatment.

	ACKNOWLEDGMENT

 
This work was supported in part by a grant from the John F. Welch/GE Fund for Cardiac Surgical Research.