Disease progression in contralateral carotid artery is common after endarterectomy☆
Article Outline
Abstract
Objective
Although the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the Asymptomatic Carotid Atherosclerosis Study (ACAS) have helped to define the role of carotid endarterectomy (CEA) for both symptomatic and asymptomatic lesions, the role of surveillance of the contralateral carotid artery remains unclear. The purpose of this study was to determine the progression of contralateral carotid artery disease with serial duplex ultrasound scans after CEA compared with the recurrent stenosis rate for the carotid artery ipsilateral to the CEA.
Methods
From January 1990 to December 2000, 473 CEA procedures were performed at a Veterans Affairs Medical Center. From this group we identified 279 patients who had undergone first-time CEA, as well as preoperative duplex scanning and postoperative duplex scanning at least once, in the vascular laboratory. At each visit stenosis of the internal carotid artery (ICA) was categorized as none (0%-14%), mild (15%-49%), moderate (50%-79%), severe (80%-99%), or occluded. Analysis of probability of freedom from progression was determined. Progression was defined as an increase in ICA stenosis 50% or greater or increase to a higher category of stenosis if baseline was 50% or greater. The Cox proportional hazards model was used for data analysis.
Results
Mean patient age was 65.7 years (range, 33-100 years). The 1024 carotid duplex ultrasound scanning examinations performed (mean, 3.7; range, 2-13) included the last study done before the index CEA and all studies done after the CEA. Mean follow-up was 27 months (range, 1-137 months). Forty-six patients were found to have contralateral carotid occlusion at initial duplex scanning, and were therefore excluded from the contralateral progression analysis. Contralateral progression was more frequent than ipsilateral recurrent stenosis at long-term follow-up (P < .01). Annual rates of “any progression” and “progression to severe stenosis or occlusion” were 8.3% and 4.4%, respectively, for contralateral arteries, and 4.3% and 2.4%, respectively for ipsilateral arteries. As a result of surveillance, 43 contralateral CEAs (19% of initial cohort) were performed. Carotid stenosis regressed in 25 arteries (10.7%). Baseline clinical and demographic factors did not predict disease progression. Baseline contralateral stenosis did not predict time to “any progression,” but was a strong predictor of “progression to severe stenosis or occlusion” (P < .001).
Conclusions
After CEA, we identified an 8.3% annual rate of progression of contralateral carotid artery stenosis and a 4.4% annual rate of progression to severe stenosis or occlusion. Baseline contralateral stenosis was significantly predictive of progression to severe stenosis or occlusion. Clinical and demographic factors were not helpful in predicting which patients would have disease progression. These data may help in assessing the cost effectiveness of duplex scanning surveillance after CEA.
Management of both symptomatic (North American Symptomatic Carotid Endarterectomy Trial [NASCET]1) and asymptomatic (Asymptomatic Carotid Atheroschlerosis Study [ACAS]2) carotid artery stenosis has been guided by use of prospective, randomized clinical trials that have demonstrated the benefit of carotid endarterectomy (CEA) in patients with high-grade lesions. However, there are fewer data regarding the natural history and management of the contralateral, asymptomatic carotid artery. While there are well-documented studies of carotid plaque progression in patients who have not undergone surgery,3, 4 the frequency with which contralateral carotid artery disease progresses to clinically significant disease has not been well-studied. Duplex ultrasound scanning, which has supplanted angiography in the preoperative evaluation of carotid artery stenosis, enables serial evaluation of the contralateral carotid artery to identify occult disease progression and also affords the opportunity to noninvasively correlate the degree of stenosis with neurologic events.3 The accuracy of duplex ultrasound scanning in evaluating carotid artery disease has been reported as having sensitivity of 99% and specificity of 84%.5, 6
We sought to review the natural history of disease progression in the contralateral carotid artery in patients who underwent CEA and were surveilled with duplex ultrasound scanning; imaging of both carotid arteries was performed at each visit. This allowed us to study both disease progression in the contralateral carotid artery and recurrent stenosis in the ipsilateral carotid artery.
Methods
The study protocol was reviewed and approved by the Institutional Review Board of the Pittsburgh Veterans Affairs Medical Center. We identified 473 patients without a history of CEA who underwent unilateral CEA at the Pittsburgh Veterans Administration Hospital between January 1990 and December 2000. A subset of 279 patients underwent preoperative duplex ultrasound scanning and postoperative ultrasound scanning at least once at the peripheral vascular laboratory at our facility. Patients with contralateral carotid artery occlusion demonstrated on the initial duplex scan were excluded from analysis of contralateral disease progression.
Preoperative duplex scanning was performed in patients considered for CEA, with the contralateral artery being routinely imaged. At each visit to the vascular laboratory a registered nurse obtained a detailed neurologic history and “yes/no” responses to questions about smoking, hyperlipidemia, diabetes, angina, and myocardial infarction. An initial postoperative study was obtained 6 months after surgery, and yearly thereafter. More frequent studies were obtained in patients whose routine studies revealed evidence of disease progression or who had neurologic symptoms. Patients were considered to have asymptomatic disease if they had no transient ischemic attacks, amaurosis fugax, or stroke in the 6 months before the preoperative study. For the last 6 to 7 years we have had a policy of offering CEA to all patients at good surgical risk with asymptomatic severe stenosis. Some patients with documented or developing severe contraleral stenosis did not undergo CEA because of patient refusal or poor surgical risk. In patients who underwent contralateral CEA, we included only duplex scan data obtained before contralateral CEA. All duplex scanning was performed by a registered vascular technologist in a fully accredited vascular laboratory, and reviewed by a vascular surgeon. Only technically adequate studies were included in the dataset. A 128 XP ultrasound machine (Acuson, Mountain View, Calif) and 5 and 7.5 MHz transducers were used. A standard protocol was used for assessing the common carotid artery (CCA), internal carotid artery (ICA), and external carotid artery. Vertebral artery flow was characterized as antegrade or retrograde, and plaque anatomy was described in terms of calcification, echogenicity, and surface quality (eg, irregular or smooth).
The degree of ICA stenosis was determined on the basis of velocity criteria and ICA-CCA ratio previously validated at our institution by means of comparison with contrast-enhanced angiography. With angiography as the gold standard, duplex ultrasound scanning was found to have sensitivity and specificity ranging from 70% to 99%, and excellent correlation in identifying stenosis (κ statistic, .85).7 At each visit stenosis of the ICA was categorized as none (0%-14%), mild (15%-49%), moderate (50%-79%), severe (80%-99%), or occluded. The relationship between ICA-CCA peak systolic velocity (PSV) ratio and corresponding degree of stenosis is shown in Table I.
Table I. Velocity criteria
| ICA/CCA PSV (cm/s) | Inferred degree of stenosis |
|---|---|
| 0.1–1.4 | None |
| 1.5–1.9 | Mild (15%–49%) |
| 2.0–3.9 | Moderate (50%–79%) |
| ≥4.0 with ICA PSV <125 | Severe (80%–99%) |
| 0 (no flow in ICA) | Occlusion |
To quantitate disease progression, we defined “any progression” as increase in ICA stenosis to 50% or greater when baseline stenosis was less than 50%, or increase to a higher degree of stenosis if baseline stenosis was 50% or greater. Therefore a transition from “none” to “mild” stenosis was not considered disease progression; all other increases in degree of stenosis were considered progression. For some analyses we examined “progression to severe stenosis or occlusion.” For patients who already had severe stenosis, this event was considered to have occurred if the carotid artery became occluded. In our determination of progression of stenosis of the ipsilateral carotid artery, we verified that carotid stenosis was reduced to “none” or “mild” with performance of the index CEA.
The Cox proportional hazards model was used for data analysis. Kaplan-Meier method plots were constructed to describe the probability of progression-free survival for ipsilateral and contralateral carotid arteries. Statistical significance was inferred at P < .05. Kaplan-Meier curves were graphed to the time point at which SEM was 10% of survival function.
Results
Of the 473 patients who underwent CEA, 279 patients (274 men, 4 women) underwent preoperative and postoperative duplex scanning. These patients had a mean age of 66 years (range, 33-100 years). Patient baseline demographic and clinical characteristics are shown in Table II. Baseline demographic and clinical characteristics were typical for patients followed up in major vascular laboratories, with the exception of the predominance of male patients in the Veterans Affairs Medical Center setting. Table II also shows the distribution of degree of initial stenosis of the contralateral carotid artery. Forty-six patients had baseline contralateral carotid artery occlusion; thus the study population included 233 patients. Nearly three fourths of patients had baseline contralateral stenosis less than 50% (Table II). A total of 1024 duplex ultrasound scanning examinations were performed (per patient: mean, 3.7; range, 2-13), including the last study done before the index CEA and all studies done after CEA. Mean follow-up was 27 months (range, 1-137 months). All duplex ultrasound scans were technically satisfactory for determination of ICA-CCA PSV ratio.
Table II. Demographic and clinical features
| Baseline patient characteristics (N = 279) | |
| Age (y) | 65.7 |
| Sex (% male) | 98.6 |
| History | |
| Angina (%) | 29 |
| Myocardial infarction (%) | 35 |
| Current smoking (%) | 41 |
| Any smoking (%) | 90 |
| Diabetes (%) | 34 |
| Hypertension (%) | 61 |
| Baseline distribution of internal carotid artery stenosis (n = 233) | |
| None/mild (%) | 73.4 |
| Moderate (%) | 14.3 |
| Severe (%) | 12.3 |
The time-dependent risk for progression was analyzed with the Kaplan-Meier method and the Cox proportional hazards model. Analysis of the probability of freedom from “any progression” and “progression to severe stenosis or occlusion” in both the carotid artery that underwent the index CEA (ipsilateral) and the contralateral carotid artery is provided in Figure 1. Contralateral progression exceeded the rate of ipsilateral recurrent stenosis during long-term follow-up (P < .01). Moreover, ipsilateral progression appeared to stabilize at roughly 3 years, in contrast to continued contralateral progression at up to 6 years of follow-up. Average annual rates of “any progression” and “progression to severe stenosis or occlusion” are shown in Table III. The annual rate of disease progression in the ipsilateral carotid artery was 4.3%, and the annual rate of progression to clinically significant stenosis (ie, severe stenosis or occlusion) was 2.4%. The annual rate of disease progression in the contralateral carotid artery was 8.3%, and the annual rate of progression to clinically significant stenosis was 4.4%. During follow-up 43 patients (19%) underwent contralateral CEA, because of either progression of contralateral carotid disease to severe or increasing PSV in patients who initially had severe disease. Of these 43 patients, 13 (30%) had symptoms attributable to carotid disease; 30 patients (70%) had no symptoms. The initial degree of carotid stenosis in these patients and the degree of stenosis before contralateral CEA are shown in Table IV. While three fourths of these patients had no or mild carotid stenosis at the initial carotid duplex scanning examination, 37% had moderate stenosis and 63% had severe stenosis at the last duplex scanning examination before CEA. Regression to a lower degree of carotid stenosis in both ipsilateral and contralateral carotid arteries was observed in 25 arteries (10.7%).
Fig 1.
Kaplan-Meier method curves show probability of being free from progression as a function of time. Raw numbers of patients analyzed in each subset at each time point are included below the figure; these were patients “at risk” for recurrent stenosis or disease progression. Analysis was continued only to a time point at which SEM was 10% of survival function.
Table III. Annual rates of ipsilateral and contralateral disease progression
| Artery | Any progression (%/y) | Progression to severe stenosis/occlusion (%/y) |
|---|---|---|
| Ipsilateral carotid | 4.3 | 2.4 |
| Contralateral carotid | ||
| Any | 8.3 | 4.4 |
| Baseline | ||
| None | 3.2 | |
| Mild | 13.3 | |
| Moderate | 5.8 |
Table IV. Progression of contralateral carotid artery stenosis from initial duplex seen to before contralateral CEA
| None | Mild | Moderate | Severe | |
|---|---|---|---|---|
| Initial | 14 | 18 | 11 | 0 |
| Final | 0 | 0 | 16 | 27 |
We used a Cox univariate proportional hazards model to analyze the predictive value of 17 variables available at the baseline study (Table V). None of these variables were predictive of either ipsilateral or contralateral disease progression. We found also that baseline contralateral stenosis did not predict time to “any progression.” However, this parameter did predict time to “progression to severe stenosis or occlusion” (P < .001). Kaplan-Meier curves showing the probability of freedom from progression to severe stenosis or occlusion as a function of baseline contralateral stenosis are shown in Figure 2.
Table V. Results of Cox proportional hazards model
| Demographic variables | |
| Age (y) | NS |
| Sex (male) | NS |
| Clinical variables | |
| Angina | NS |
| Blood pressure | |
| Systolic >160 mm Hg | NS |
| Diastolic >90 mm Hg | NS |
| Diabetes | NS |
| Hypertension | NS |
| Smoking status | |
| current smoker | NS |
| previous smoker | NS |
| Myocardial infarction | NS |
| Amaurosis fugax | NS |
| Vertigo episodes | NS |
| Syncopal episodes | NS |
| Headaches | NS |
| Hemiplegia | NS |
Fig 2.
Kaplan-Meier method curves show effect of baseline contralateral stenosis on the probability of being free from “progression to severe stenosis or occlusion” in the contralateral carotid artery. In patients with baseline severe stenosis, progression indicates development of carotid occlusion. Raw numbers of patients analyzed in each subset are included below figure.
Discussion
Several early studies that examined progression of contralateral carotid artery disease after ipsilateral CEA were performed before publication of randomized clinical trials such as ACAS and the Veterans Affairs Cooperative Study Group,8 which suggested a benefit from CEA over medical treatment in patients with asymptomatic carotid artery stenosis. These early studies9, 10, 11 suggested operative management only in patients with symptomatic carotid disease. ACAS showed that for patients without symptoms with stenosis greater than 60% the aggregate risk reduction over 5 years for ipsilateral stroke and any perioperative stroke or death was 53% with surgery versus medical therapy. These data lend support to the concept of using carotid duplex scanning surveillance, either as a one-time study or serially, to identify severe or progressive asymptomatic stenosis. However, it is not clear whether duplex surveillance is cost-effective. It is highly unlikely that surveillance is cost-effective for the entire population, but it may be useful under certain conditions in specific patient groups.12, 13, 14, 15 One subset in which serial duplex scanning surveillance may be of value is the group of patients who have undergone unilateral CEA. These patients may reasonably be expected to be at increased risk for stenosis on the opposite side. However, previous studies of the value of serial duplex scanning after unilateral CEA have reached conflicting conclusions.16, 17, 18, 19
In this study, we did not have access to reliable data regarding patient symptoms during follow-up after CEA. However, other studies indicate that disease progression does not consistently correlate with development of symptoms. Roederer et al3 reported that, while disease progression to clinically relevant stenosis was associated with symptoms on the appropriate side in 18% of contralateral carotid arteries, symptoms developed in 8% of patients without evidence of progression on duplex ultrasound scans. Similarly, Norrving et al20 compared arteries not operated on in which disease progressed with those without progression, and found the proportion of symptom-related sides to be 18% and 4%, respectively. We had no access to data concerning use of antihypertensive medications in our patients. Unless contraindicated, most of our patients were given maintenance aspirin therapy. Use of lipid-lowering agents was implemented at the Veterans Affairs Medical Center in the mid-1990s, which makes it difficult to draw conclusions for the study population, inasmuch as the study encompassed the time from 1990 through 2000. Nonetheless, data regarding the natural history of carotid artery disease progression and threshold for surgical intervention are important in this era of aggressive medical therapy for cardiovascular risk factors, which includes use of anti-platelet and lipid-lowering agents.
In this study, the annual rate of ipsilateral recurrent stenosis was 4.3%, and the annual rate of progression to clinically significant recurrent stenosis (ie, severe or occluded) was 2.4%. This is consistent with published reports.21, 22, 23 Further, annual rate of disease progression in the contralateral carotid artery was 8.3%, and annual rate of progression to clinically significant stenosis was 4.4%. Nineteen percent of this cohort subsequently underwent CEA. Further evaluation of the 43 patients who underwent contralateral CEA revealed that 70% of these patients had no symptoms and underwent CEA on the basis of increasing carotid stenosis. This finding supports the role of duplex scanning surveillance after CEA, given that three fourths of these patients had either no or mild stenosis at initial duplex scanning. At CEA, all patients had either moderate or severe stenosis.
Baseline stenosis was a strong predictor of time to “progression to severe stenosis or occlusion.” Of interest, degree of baseline stenosis did not predict time to “any progression” in the contralateral carotid artery. These data indicate that disease progression per se occurs independent of baseline stenosis. However, patients with more advanced disease at baseline are more likely to have clinically significant stenosis over any given period of observation. These results are similar to those reported by others.16, 24 We could not identify any clinical risk factors associated with contralateral disease progression; therefore clinical criteria cannot be used to identify subgroups at high risk for progression. Nearly three fourths of patients had baseline contralateral stenosis less than 50%, indicating that our results are not skewed by a preponderance of advanced contralateral disease at the outset. Of note, the male preponderance in our patient population makes it difficult to extrapolate our results to female patients.
Our data suggest that contralateral disease progression is relatively common. If it is assumed that the patient is considered a candidate for CEA because of asymptomatic severe stenosis, the goal of duplex scanning surveillance is to identify development of severe stenosis. We believe that patients can be adequately monitored with duplex scanning according to the degree of initial contralateral stenosis. For stenosis less than 50%, annual or even biennial duplex ultrasound scanning is adequate. For stenosis greater than 50%, the high frequency of progression to severe stenosis or occlusion warrants surveillance every 6 months once the early postoperative study has ruled out technical complications or early recurrent stenosis of the ipsilateral carotid artery.
Our data do not enable us to make any definitive comments about the cost-effectiveness of the strategy described. However, a recent decision-analysis study12 concluded that the cost-effectiveness ratio of serial duplex ultrasound scanning was acceptable in a population of patients with a rate of progression to severe stenosis of 6% per year. Our overall cohort had a 4.4% annual rate of progression to contralateral severe stenosis or occlusion. This rate was substantially higher, and exceeded the 6% threshold among patients with baseline stenosis greater than 50% (Fig 2). In this subset of our cohort, duplex ultrasound scanning surveillance would appear to be cost-effective.
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☆ Competition of interest: none.
PII: S0741-5214(03)01220-5
doi:10.1016/j.jvs.2003.08.016
© 2004 The Society for Vascular Surgery and The American Association for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
