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Head and Neck Imaging |
1 From the Departments of Angiology (M.S., R.A., S.S., E.M.), Laboratory Medicine (M.E., W.M., H.R., O.W.), and Clinical Neurology (W.L.), University of Vienna, Medical Faculty, Währinger Gürtel 18-20/6J, A-1090 Vienna, Austria. Received March 1, 2002; revision requested April 25; final revision received August 29; accepted September 24. Address correspondence to M.S. (e-mail: martin.schillinger@akh-wien.ac.at).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: One hundred eight consecutive patients with 70% or greater stenosis of the internal carotid artery (ICA) according to the North American Symptomatic Carotid Endarterectomy Trial criteria underwent successful stent implantation in the ICA in a prospective cohort study. Six-month patency was evaluated at color-coded duplex ultrasonography. The association between in-stent restenosis (
50%, North American Symptomatic Carotid Endarterectomy Trial criterion) and C-reactive protein (CRP) and serum amyloid A levels at baseline and at 24 and 48 hours after intervention was assessed.
RESULTS: Restenosis was found in 15 (14%) patients within 6 months. CRP level at 48 hours, exemplary for the postintervention acute-phase response, was significantly (P = .01) associated with 6-month restenosis by using multiple logistic regression analysis. Recurrent stenosis after prior stent implantation in the carotid artery (odds ratio, 9.2; 95% CI: 1.6, 53.2; P = .01) and residual stenosis of 10%–30% after stent implantation (odds ratio, 9.7; 95% CI: 1.6, 59.3; P = .01) were independent clinical predictors of restenosis.
CONCLUSION: Extent of vascular inflammatory response after stent implantation in the carotid artery measured with acute-phase reactants is associated with 6-month patency. Recurrent stenosis after prior stent implantation and initial suboptimal technical result seem to be clinically relevant predictors of postangioplasty outcome.
© RSNA, 2003
Index terms: Arteries, restenosis, 172.72, 904.721 • Arteritis, 172.2581, 904.29, 904.458 • Carotid arteries, interventional procedures, 172.1269, 904.1268 • Carotid arteries, stenosis or obstruction, 172.72, 904.721
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Stent implantation applies a transient strain to the vessel wall that activates vascular smooth muscle cells and endothelial cells and initiates an inflammatory and proliferative phase of vessel repair (5). Excessive vascular smooth muscle cell proliferation and migration through the meshes of the stent and hypertrophic neointima formation may lead to recurrent lumen narrowing and in-stent restenosis. The vascular inflammatory response can be measured by means of determining the postintervention course of acute-phase reactants (6,7). These circulating markers of inflammation reflect the activity of an underlying process, with macrophage accumulation and cell proliferation (8). In particular, the plasma proteins C-reactive protein (CRP) and serum amyloid A (SAA) are sensitive fast-reacting markers of acute-phase reaction (9–11) and provide an indirect measure of a cytokine-dependent inflammatory process of the arterial wall (12,13). Serum levels of acute-phase reactants are related to atherosclerosis in the carotid arteries (14); however, their prognostic effect on restenosis after stent implantation in the carotid artery has not been investigated to date, to our knowledge. We hypothesized that postintervention serum levels of acute-phase reactants would be associated with recurrent lumen narrowing after stent implantation in the carotid artery. Therefore, the aim of the present study was to determine the prognostic importance of periintervention serum levels of acute-phase reactants in 6-month restenosis after stent implantation in the carotid artery.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Inclusion and Exclusion Criteria
The indications for stent implantation in the carotid artery that were applied in the present study, as accepted by the ethics committee of our medical faculty, have been published previously (1). In short, patients with symptomatic stenosis in the ICA greater than 70% according to the North American Symptomatic Carotid Endarterectomy Trial criteria and quantified angiographically and asymptomatic patients with stenosis greater than 90% were eligible for inclusion. We excluded patients who were severely disabled as a result of stroke or dementia, patients with acute metabolic dysfunction or renal insufficiency who were not undergoing dialysis, as well as patients with an intracranial tumor or a cerebral hemorrhage as indicated by using cranial computed tomography (CT). Within the study period, 111 patients were scheduled for stent implantation in the carotid artery. Three (3%) of 111 patients were excluded because of primary technical failure. In 108 (97%), primary technical success was achieved, and these 108 patients were included in the final analysis. The median age was 70 years, and the interquartile range (IQR), from the 25th to the 75th percentile, was 64–75 years. Seventy-three (68%) of 108 patients were men (median age, 69 years; IQR, 63–76 years), and 35 (32%) were women (median age, 71 years; IQR, 64–75 years).
Definitions
Diabetes mellitus was classified in patients with a fasting blood glucose level greater than 110 mg/dL (6.1 mmol/L) measured on three occasions, in patients with oral glucose tolerance test results suggestive of disease, and in patients with a glycosylated hemoglobin A1c level greater than 0.06 (6.5%). Hyperlipidemia was classified in patients with a fasting total serum cholesterol level greater than 200 mg/dL (5.17 mmol/L), a serum low-density lipoprotein value greater than 130 mg/dL (3.36 mmol/L), or a serum triglyceride value of greater than 180 mg/dL (2.03 mmol/L), and it was considered to be present in all patients receiving lipid-lowering medication. Arterial hypertension was classified in patients with blood pressure values greater than 135/85 mm Hg in at least one-third of 30 measurements. Coronary arterial disease was categorized according to the Canadian Cardiovascular Society classification, and routine evaluation included stress exercise testing, myocardial scintigraphy, and coronary angiography in selected cases. Peripheral arterial disease was evaluated with clinical history, oscillographic findings, ankle brachial index measurements, and duplex ultrasonographic (US) findings and was classified as present (Fontaine stage I or II) or absent. No patient with acute (Fontaine stage III) or chronic (Fontaine stage IV) critical limb ischemia was eligible for stent implantation in the carotid artery during the study period.
Primary technical success was classified in patients with a residual stenosis less than 30% at the treated segment calculated from the final angiogram. Residual stenosis was categorized as a remaining diameter reduction of 10%–30% at the vessel segment with stent implantation. In-stent restenosis was defined as 50% or greater diameter reduction at the vessel segment with stent implantation within the first 6 months after stent implantation in the carotid artery measured by using color-coded duplex US.
Duplex US Evaluation
Duplex US grading of the stenosis of the carotid artery was performed in accordance with the principles of the consensus meeting concerning the quantification of stenosis of the extracranial carotid artery (15) and the proposals of Nicolaides et al (16). In short, systolic and diastolic flow parameters in the common and internal carotid arteries were documented, and the following ratios of the carotid artery were calculated (15,16): the ratio of the peak systolic velocity (PSV) in the ICA and the PSV in the common carotid artery (CCA) (PSVICA/ PSVCCA), the ratio of the PSV in the ICA and the end-diastolic velocity (EDV) in the CCA (PSVICA/EDVCCA), and ratio of the EDV in the ICA and the EDV in the CCA (EDVICA/EDVCCA). A combination of these flow factors was then used to calculate the grade of the stenosis in the ICA that corresponded to the North American Symptomatic Carotid Endarterectomy Trial angiographic criteria of stenosis in the ICA (16). The cutoff for in-stent restenosis of 50% or greater was classified as a combination of PSVICA greater than 1.5 m/sec and a PSVICA/PSVCCA ratio greater than 2.5. We used a US scanner (XP 10; Acuson, Mountain View, Calif) with a 5-MHz linear probe for duplex US investigations before the intervention and at 1 day and at 6 months after the intervention. All duplex US evaluations were performed by experienced medical technicians who were blinded with regard to the patient’s clinical and laboratory data with the supervision of one of the authors (E.M.).
Neurologic Evaluation
A complete neurologic history and the patient’s National Institutes of Health Stroke Scale status (17) were routinely assessed by an independent neurologist (W.L.) before the intervention. Cranial CT was mandatory before the intervention; routine clinical neurologic examinations were scheduled at the day before and at the day after intervention and at day 30. In cases in which the patient was suspected of having a neurologic event, an instant clinical neurologic examination including cranial CT and reexaminations as clinically necessary were performed. Neurologic events were categorized as transient ischemic attacks, minor stroke, and major stroke.
Patient Data
At admission, the patient’s medical history and data from the physical examination were recorded with a standard questionnaire by two observers in consensus (M.S., W.M.). Routine laboratory values, urinalysis results, and chest radiographic findings were used to exclude coexistent inflammatory diseases. Clinical history and physical examination were evaluated with special attention to cardiovascular risk factors and comorbidities as follows: age; sex; current history of smoking; presence of hyperlipidemia, arterial hypertension, diabetes mellitus, peripheral arterial disease, and coronary arterial disease; history of cerebrovascular events; current use of medications; and prior ipsilateral or contralateral stent implantation in the carotid artery.
Interventions in the Carotid Artery
All stent implantations were performed according to a previously published protocol by one physician (R.A.) who had experience with more than 300 interventions in the carotid artery before initiation of this study (1). Before angioplasty, patients received 5,000 IU of heparin intraarterially. Location, length, and grade of the target lesion were derived from the initial angiogram by the interventionist. An over-the-wire stent (Carotid Wallstent OTW; Boston Scientific, Natick, Mass) was implanted in the carotid artery in all patients without use of a cerebral protection device. The size of the stent was selected according to the estimated diameter of the ICA at selective angiography. The length, diameter, and number of stents were recorded. Duration of fluoroscopy (time from obtaining the initial aortic overview angiogram until obtaining the final selective angiogram of the ICA after the intervention) and the dose of contrast material (median dose, 210 mL [IQR, 180–240 mL] administered intraarterially) were recorded. We used the nonionic low-osmolality contrast agent ioversol (Optiray 320; Mallinckrodt, St Louis, Mo) in a dilution of 1:1 for all interventions.
After stent implantation, immediate selective follow-up angiography in at least two planes was performed to evaluate the local result and to examine the intracranial arteries with respect to changes of hemodynamics or signs of embolization. Postintervention intracranial runoff was categorized subjectively by two independent, but not blinded, observers (M.S., W.M.) as "improved" in patients with enhanced filling of the intracranial vessel compared with findings on the initial angiogram, as "unchanged" in patients with intracranial vessel-filling similar to findings on the initial angiogram, and as "embolization" in patients with angiographic signs of distal emboli. In cases of a suboptimal result at immediate follow-up angiography, a second stent was implanted. Standard antiplatelet therapy included 75 mg of clopidogrel bisulfate (Sanofi Pharma Bristol-Myers Squibb, Paris, France) and 100 mg of acetylsalicylic acid daily for 4 weeks. Thereafter, therapy with clopidogrel at the same dose daily without acetylsalicylic acid was continued. Periintervention and postintervention complications at the site of arterial puncture and at the dilated vessel segment were documented up to 48 hours after the intervention. Angiographic data and complications were recorded by an observer (M.S. or W.M.) other than the interventionist.
Laboratory Investigations
Routine laboratory investigations, including hemoglobin A1c level, low-density lipoprotein cholesterol level, complete blood cell count, and serum creatinine level, were performed at baseline before stent implantation in the carotid artery. Antecubital venous blood samples were obtained for determination of CRP and SAA values before the intervention and at 8, 24, and 48 hours after the intervention. For measurement of serum CRP values, the high-sensitivity assay (N Latex CRP Mono; Dade Behring, Vienna, Austria) was used. The SAA value was measured by using a high-sensitivity assay (N Latex SAA; Dade Behring). The detection levels of high-sensitivity CRP and SAA assays were 0.03 mg/dL (0.3 mg/L) and 3.8 mg/L (3.8 U/L), respectively, and the coefficients of variation were 4.6% and 6.4%, respectively. All laboratory measurements were performed with supervision of one of the authors (M.E. or H.R.).
Follow-up
Patients were followed up for 6 months in the outpatient clinic to analyze the occurrence of restenosis and cerebrovascular events: Evaluation of patient complaints and findings at physical reexamination and color-coded duplex US were performed at 6 months in all patients. Follow-up investigations were performed with supervision of one of the authors (E.M.).
Statistical Analysis
Data are presented as the median and the IQR (range, 25th to 75th percentile). Percentages were determined for dichotomous variables. The 
2 test was used to compare proportions. For univariate comparison of continuous data, the Mann-Whitney U test was used. Nonparametric Friedman analysis was used for analysis of repetitive measurements. For univariate analysis, all variables recorded from the patient’s medical history, the initial angiograms, and the technical angiographic data were evaluated as possible risk predictors. Multiple logistic regression analysis was then applied to assess the independent effect of the acute-phase reactants on 6-month patency, while adjustment was performed for the potentially confounding effects of other baseline variables. Baseline variables were selected for the model if they (a) had a clinically or biologically plausible relationship with the outcome or (b) appeared to be imbalanced between patients with and patients without restenosis, which was indicated by a P value less than .2. Results of the logistic regression model were presented as the odds ratio and the 95% CI. Interaction was assessed by using additive and multiplicative interaction terms, the linearity of the logit assumption was checked for continuous predictor variables, and an analysis of residuals was performed. Regression diagnostics and overall model fit were performed according to standard procedures (18). All P values were calculated as two sided; a P value less than .05 was considered to indicate a statistically significant difference. Calculations were performed with statistical software (SPSS for Microsoft Windows, version 10.0; SPSS, Chicago, Ill) by one of the authors (M.S.).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Follow-up Data
Recurrent lumen narrowing at the treated segment with an in-stent restenosis of 50% or greater was found in 15 (14%) of 108 patients during the first 6 months after stent implantation in the carotid artery. Three (3%) of 108 patients had a 70% or greater restenosis; one of these patients remained asymptomatic and two patients had a major stroke (one of them died). All 12 patients with restenotic lesions with a 50%–60% stenosis remained asymptomatic. Clinical characteristics of patients with and patients without restenosis are presented in Table 1. With univariate analysis, the following characteristics were associated with the occurrence of in-stent restenosis: patient’s age, history of ipsilateral cerebral infarction, recurrent in-stent stenosis after prior stent implantation in the carotid artery, and residual stenosis after stent implantation. Longer lesions in the ICA were also more frequently found in patients with restenosis, but this association did not indicate a significant difference at the 5% level (Table 1).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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The rate of in-stent restenosis in the present series seems to be high; however, restenosis was defined as 50% recurrent lumen diameter reduction, according to flow factors at the segment with stent implantation, in contrast to the definition in former studies with a cutoff value of 70% restenosis. Nevertheless, the frequency of 3% of patients with restenosis of 70% or greater compares well with previously published data (1,2), and high-grade symptomatic restenosis after stent implantation in the ICA remains a rare complication.
The pathophysiology of the vascular wall reaction after stent implantation is not entirely resolved. It is a well-known notion that intimal and medial injury from stent implantation cause a perivascular inflammatory response (19,20), and the severity of arterial injury during stent placement correlated with increased inflammation (20). Findings at histologic studies showed that endothelial and medial damage and lipid core penetration of the stent struts are responsible for the local inflammatory response (8). The vascular inflammatory process is suggested to stimulate vascular smooth muscle cell proliferation and constrictive neointimal growth (21,22), a process that has been referred to as a manifestation of wound healing expressed specifically in vascular tissue (23). Vascular smooth muscle cell proliferation and hypertrophic neointima formation finally lead to in-stent restenosis. The extent of the inflammatory process after stent implantation in the peripheral and coronary arteries can be quantified by means of postintervention measurement of acute-phase reactants (6,7). Postintervention serum levels of CRP were associated with in-stent restenosis after coronary angioplasty (6). Our findings support the hypothesis that stent implantation in the carotid artery also induces a marked vascular inflammatory response that is measurable with systemic levels of acute-phase reactants. The acute inflammatory process after stent implantation in the carotid artery seems to be a hallmark in the development of restenosis (8,20,24), since patients with a more extensive increase in levels of acute-phase reactants were more likely to develop restenosis. However, the acute-phase response is a nonspecific phenomenon that may be induced by almost all kinds of tissue damage, inflammation, or systemic stress (10). So far, it is unclear whether acute-phase reactant levels are increased as a consequence of the disease or causally contribute to its progression. One reason for a causal role could be the activation of the complement system, local vascular inflammatory reactions, and subsequent tissue damage (25). Thus, it may be worth examining experimentally whether inflammatory modifiers such as statins can reduce the rate of in-stent restenosis.
Clinical risk factors for in-stent restenosis in the carotid artery hardly have been identified as yet. Recurrent stenosis after prior stent implantation and suboptimal technical result in terms of residual stenosis at the segment with stent implantation were associated with 6-month postangioplasty outcome in this patient series. The thromboembolic risk from surface plaques of the restenotic lesion is suggested to be low, since, unlike the primary atherosclerotic lesion, the restenotic lesion exhibits a smooth surface. Therefore, hemodynamic evaluation of the patient’s cerebral flow reserve, for example with perfusion magnetic resonance angiography, may help to identify patients with restenosis who may benefit from redilation of the in-stent restenosis. Otherwise patients with restenosis may be candidates for conservative treatment unless the restenotic lesion becomes symptomatic. Patients with suboptimal initial technical results in terms of residual stenosis after stent implantation in the carotid artery had an almost 10-fold increased risk for short-term restenosis. Achievement of an optimal technical result thus seems to be crucial for the patient’s outcome. Nevertheless, the prognostic impact of these clinical factors has to be evaluated and confirmed in larger patient series.
Angiography is generally considered the reference standard for quantification of stenosis of the ICA. However, angiography of the aortic arch and selective angiography of the ICA are associated with a considerable periintervention risk of neurologic complications and complications at the site of arterial puncture. Therefore, in the present study, noninvasive color-coded duplex US was used for follow-up and quantification of in-stent restenosis. Sensitivity, specificity, inter- and intraobserver variability of duplex US grading, and correlation with angiographic findings have been shown to be excellent by numerous investigators (15,16,26–33), and the use of this method for determination of the end point of the study seemed justified.
We were able to identify predictors of restenosis in the multiple regression models, but the 95% CIs for the odds ratios of the clinical variables were wide because of the small number of patients with restenosis. Furthermore, although serum levels of acute-phase reactants and their relative increase within 48 hours after intervention were associated with outcome, the odds ratios in the multiple regression models indicated only a small incremental increase of risk. Therefore, we can conclude that the acute-phase reaction after stent implantation in the ICA is associated with restenosis, but larger patient samples will be needed to determine cutoff values of acute-phase reactants for clinical risk prediction.
In conclusion, the extent of the vascular inflammatory response measured with serum levels of acute-phase reactants after stent implantation in the carotid artery was associated with short-term restenosis. Recurrent stenosis after prior stent implantation in the carotid artery and initial suboptimal technical result seem to be clinically relevant predictors of postangioplasty outcome.
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FOOTNOTES |
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Abbreviations: CCA = common carotid artery, CRP = C-reactive protein, EDV = end-diastolic velocity, ICA = internal carotid artery, IQR = interquartile range, PSV = peak systolic velocity, SAA = serum amyloid A
Author contributions: Guarantors of integrity of entire study, E.M., M.S.; study concepts, M.S., M.E., H.R., W.L., O.W., E.M.; study design, M.S., W.M., R.A., S.S.; literature research, M.S.; clinical studies, R.A.; data acquisition, M.S., W.M., M.E.; data analysis/interpretation, all authors; statistical analysis, M.S.; manuscript preparation and editing, M.S.; manuscript definition of intellectual content, revision/review, and final version approval, all authors.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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