JOURNAL OF VASCULAR SURGERY834 Lal et al November 2007 The patterns of ISR developing after carotid artery to standard techniques used by our group previously4,5,16stenting have not been described, and their prognostic to estimate the degree of stenosis. Velocity criteria forutility has not been studied. We therefore developed an native carotid arteries (peak systolic velocity 130 cm/s)ultrasound classiﬁcation scheme for post-CAS ISR based on were used to identify potential patients with ISR. Thesethe length and distribution of the lesion with respect to the underwent detailed B-mode imaging with power Dopplerstent and veriﬁed its accuracy with carotid angiography. We to select arteries with any ISR 40%. These lesions werethen assessed long-term clinical follow-up to determine ﬁnally included in the present analysis; therefore, onlywhether the classiﬁcation system predicted the need for patients with conﬁrmed visible restenotic lesions were in-future therapeutic reintervention in the form of target cluded in the study. This strategy ensured that we did notlesion-site revascularization (TLR). miss any patients with ISR. B-mode imaging studies during follow-up were furtherMETHODS used to deﬁne the morphology of the ISR lesions according Patient population and treatment. We performed to the length and distribution of the lesion with respect to255 CAS procedures from January 1, 1996, through De- the stent. Standard imaging techniques used previously bycember 31, 2006. Lesions were treated with a WallStent our group were applied to obtain grayscale images of the(Boston Scientiﬁc Corp, Natick, Mass) or ACCULINK ipsilateral cervical carotid artery.5 The transducer wasstent (Guidant Corp, St. Paul, Minn). Procedural details placed directly over the stented carotid artery segment tofor CAS at our institution have been published in detail by obtain a longitudinal image. It was then swept from theour group previously.1-5 base of the neck to the angle of the mandible to obtain All patients received aspirin (325 mg daily) and clopi- multiple cross-sectional images of the entire common anddogrel (75 mg twice daily) for at least 48 hours before the internal carotid arteries. The images were recorded onprocedure. Clopidogrel (75 mg daily) was continued for 30 magneto-optical (MO) disks and analyzed off-line with adays after the procedure, and aspirin was continued indeﬁ- computer-assisted image-analysis program (Metamorphnitely. 6.1, Universal Imaging Corp, Downingtown, Pa) by inde- Patients early in our experience underwent CAS with- pendent observers blinded to clinical ﬁndings. The longi-out embolic protection. The ACCUNET (Abbot, Menlo tudinal image was used to measure the length of the lesion,Park, Calif) antiembolic device was used in all subsequent deﬁned as the distance from the proximal shoulder to thepatients. At last follow-up, 85 arteries developed ISR of distal shoulder of the lesion, and to determine its location 40% and constitute the cohort for the current study. with respect to the stent. The cross-sectional views were Patients underwent endovascular retreatment when used to determine the luminal diameters.their ISR reached a threshold of 80%, regardless of neu- Classiﬁcation of in-stent restenosis. B-mode imagesrologic symptoms. Devices used to treat ISR included in longitudinal and serial cross sections were reviewed byballoon angioplasty, cutting balloon angioplasty, and re- two independent observers who classiﬁed the lesions onstenting and were selected at the discretion of the treating separate occasions (Fig 1). Disagreements were resolved byphysician. No patient required surgical revascularization for consensus.ISR. Lesions after the ﬁrst recurrence were excluded from ● Type I (focal end-stent group): Lesions are 10 mmthe primary analysis to avoid introducing any statistical bias long and are positioned at the proximal or distal mar-in the multivariate model. gin (but not both) of the stent. Lesions 10 mm long Demographics and follow-up. Clinical demograph- at both ends of the stent are deﬁned as type I, multi-ics and laboratory results were collected in a prospective focal end-stent.registry. Risk factors that were tabulated included coronary ● Type II (focal intrastent group): Lesions are 10 mmartery disease (currently or previously symptomatic, requir- long and are conﬁned to within the stent(s) withouting intervention), medically treated diabetes mellitus, med- extending outside the margins. Two or more discreteically treated hypertension, medically treated hypercholes- lesions 10 mm in length located within the stent areterolemia (or if serum cholesterol was 180 mg/dL), and deﬁned as type II, multifocal intrastent.smoking (current or prior smoker). Clinical follow-up was ● Type III (diffuse intrastent group): Lesions are 10performed with ofﬁce visits and duplex ultrasound exami- mm long and are conﬁned to within the stent(s) with-nations. The occurrence of TLR events was recorded. out extending outside the margins. Ultrasound examination. Duplex ultrasound exami- ● Type IV (diffuse proliferative group): Lesions are 10nations, including Doppler velocity measurements and B- mm long and extend beyond the margin(s) of themode imaging studies, were performed in our noninvasive stent(s).vascular laboratory, which is approved by the Inter-societal ● Type V (occlusion group). Lesions have no progradeCommission on Accreditation of Vascular Laboratories,15 ﬂow and no lumen is identiﬁed.before and after CAS within 3 days of the procedure andduring each annual follow-up visit. The studies were per- Angiographic analysis. The angiographic percentageformed with a 7-13 MHz linear array transducer (Sequoia of stenosis was measured before and after stent deployment in512, Acuson, Mountain View, Calif). Doppler velocities all patients undergoing CAS and was based on standard tech-were obtained with appropriate angle correction according niques using multiple projections. All angiograms were ana-
JOURNAL OF VASCULAR SURGERYVolume 46, Number 5 Lal et al 835 Fig 1. A, Schematic images show the ﬁve patterns of carotid in-stent restenosis based on the introduced classiﬁcation. The shaded area represents the stent. B, Representative B-mode ultrasound images of in-stent restenosis correspond to the patterns I through IV.lyzed off-line with a computer-assisted quantitative edge- (NASCET) criteria.17 The in-stent least luminal diameterdetection algorithm (MDQM; MEDCON Telemedicine was compared with the distal nontapering portion of theTechnology, Inc, Livingston, NJ) by an independent observer internal carotid artery, which served as the reference seg-who was blinded to the ultrasound and clinical ﬁndings. In 13 ment. Lesion length was measured as the distance from thearteries, ISR 80% was found and they underwent TLR. In proximal shoulder to the distal shoulder of the lesion. The15 additional ISR lesions, conﬁrmatory angiography was done angiographic lesion length was compared with that ob-for progressively increasing velocity measurements on ultra- tained by B-mode imaging.sound imaging and these were found to be 80% diameter- Statistical analysis. Statistical analysis was performedreducing lesions. Preprocedural B-mode imaging was com- using GraphPad Prism 3.00 software (GraphPad Softwarepared with angiography in these patients to test the accuracy Inc, San Diego, Calif) and SPSS software (SPSS Inc, Chi-of our classiﬁcation scheme. cago, Ill). Categoric data are presented as percentages and Angiographic stenosis was determined using North continuous data as mean SD. Categoric data were com-American Symptomatic Carotid Endarterectomy Trial pared using the 2 test, and continuous data were com-
JOURNAL OF VASCULAR SURGERY836 Lal et al November 2007Table I. Baseline patient characteristics Patterns of in-stent restenosis by type I, focal end-stent II, focal intrastent III, diffuse intrastent IV, diffuse proliferativeCharacteristic* (n 34) (n 22) (n 11) (n 17)Distribution 40.0 25.9 12.9 20.0Age, y 73.9 9.4 74.6 6.7 70.5 6.7 69.2 15.9Male sex 61.8 63.6 63.6 70.6Diabetes mellitus† 20.6 22.7 45.5 52.9Hypertension 85.3 86.4 81.8 70.6Coronary artery disease 67.6 45.5 45.5 47.1Hypercholesterolemia 64.7 72.7 63.6 64.7Smoking 41.2 45.5 44.2 29.4*Categoric variables expressed as percentage; continuous variables as mean SD.† P .02.Table II. Characteristics of the original treated lesion Patterns of in-stent restenosis by type I, focal end-stent II, focal intrastent III, diffuse intrastent IV, diffuse proliferative Etiology of treated lesion* (n 34) (n 22) (n 11) (n 17)In-stent restenosis† 2.94 0 0 41.2Primary atherosclerosis‡ 38.2 72.7 36.4 23.5Post CEA-restenosis 58.8 27.3 63.6 35.3Severity of treated lesion, % stenosis 81.9 82.5 88.9 83.5Preprocedure neurologic symptoms 29.4 22.7 27.3 23.5Details of implanted stents Stents/lesion 1.1 0.4 1.1 0.3 1.2 0.4 1.3 0.5 Length, mm 28.8 10.3 31.4 8.3 30.0 6.3 28.2 11.7 Types of implanted stents§ Wallstent 50.0 36.4 27.3 47.1 Acculink 50.0 63.6 72.7 52.9Post-treatment result, % residual stenosis 6.4 7.6 7.1 6.8 6.9 7.3 7.7 8.3CEA, Carotid endarterectomy.*Values are expressed as percentages, continuous variables are expressed as mean SD† P .003.‡ P .02.§ P .03.pared using analysis of variance with the Tukey post-test. P according to our proposed scheme, 40% (n 34) were .05 was considered signiﬁcant. focal end stent (type I), 25.9% (n 22) were focal intras- The primary end point of the analysis was the associa- tent (type II), 12.9% (n 11) were diffuse intrastent (typetion of lesion classiﬁcation with TLR. Univariate variables III), 20% (n 17) were diffuse proliferative, and 1.2% (nwith P .2 were entered into the multivariate logistic 1) developed an occlusion. Inter-rater agreement for theregression model; forward stepping was used to determine assignment of lesion type based on ultrasound imaging wasthe independent predictors of TLR. Independent variables 0.88 (very good).were considered signiﬁcant risk factors at P .05. To Baseline patient characteristics are presented in Table I.conﬁrm the accuracy of the classiﬁcation scheme, ISR le- None of the patients had neurologic symptoms in associa-sion length measurements derived from duplex ultrasound tion with the development of ISR. All groups were wellimaging were compared with angiographic measurements matched with respect to age and sex and for associatedusing linear regression. Inter-rater agreement on the ultra- comorbidities such as a history of hypertension, coronarysound classiﬁcation was assessed by calculating the statis- artery disease, hypercholesterolemia, and smoking. How-tic; a score of 0.81 to 1.0 was deﬁned as very good agree- ever, increasing levels of ISR classiﬁcation were associatedment. with an increasing prevalence of diabetes mellitus (20.6%, 22.7%, 45.5%, and 52.9% for types I to IV, respectively; 2RESULTS trend, 5.4; P .02). Patient characteristics. Of the 255 CAS procedures Lesion characteristics. The severity (degree of steno-performed, ISR developed in 85 arteries during a mean sis) of the original lesion treated with CAS was comparablefollow-up of 19.3 months. Of these 85 ISR lesions classiﬁed in all ISR classes, as indicated in Table II. The proportion of
JOURNAL OF VASCULAR SURGERYVolume 46, Number 5 Lal et al 837Table III. Target lesion revascularization Patterns of in-stent restenosis by type I, focal end-stent II, focal intrastent III, diffuse intrastent IV, diffuse proliferativeVariables* (n 34) (n 22) (n 11) (n 17)Incidence of TLR, %* 0 0 27.3 58.8Devices used for ISR, No. Balloon angioplasty 0 0 1 3 Stent 0 0 1 5 Cutting balloon 0 0 0 1 Cutting balloon stent 0 0 1 1Post-treatment result, % residual stenosis N/A N/A 10.4 6.9 11.9 6.1TLR, Target lesion revascularization; ISR, in-stent-restenosis; N/A, not applicable.*P .001.lesions treated for neurologic symptoms, the number ofstents used per lesion, and the mean stent length used werealso similar across ISR types. Technical success wasachieved in all patients and no differences were noted in theangiographic residual stenosis after therapy across all ISRtypes. In this cohort, 37 patients had been treated with aWallStent and 48 with an Acculink stent. The incidence ofISR did not vary with the type of stent used or the type oflesion treated. Univariate analysis indicated a difference inthe patterns of ISR between stent types. Intrastent ISRpatterns (types II and III) occurred more frequently afterplacement of Acculink stents compared with WallStents(P .03). Univariate analysis also indicated that focalintrastent (type II) lesions occurred more frequently aftertreatment of primary atherosclerotic carotid stenosis com- Fig 2. Linear regression analysis shows comparison of lesion length measurement by quantitative angiography vs B-mode ultra-pared with treatment for post-CEA restenosis (P .02). sound imaging. Finally, 13 patients had recurrent ISR, of which threewere type III lesions and the remaining 10 were type IV.On univariate analysis, higher levels of ISR classiﬁcation the accuracy of our proposed ultrasound classiﬁcation ofwere associated with prior ISR (2.9%, 0%, 0%, and 41.2% ISR based on lesion length measurements (r2 0.82, linearfor types I to IV, respectively; 2 trend, 13.3; P .003). regression; Fig 2). Target lesion revascularization. Endovascular re- Multivariate analysis. We introduced diabetes, coro-treatment was required in three of 11 patients with type III nary artery disease, neurologic symptom status, recurrentISR, and in 10 of 17 patients with type IV ISR (Table III). ISR and primary atherosclerosis etiologies, stent type, stentThe mean interval between CAS and TLR was 18.2 number, and the pattern of ISR according to the intro-months. We observed a signiﬁcant increase in TLR in duced B-mode ultrasound classiﬁcation in a stepwise mul-association with increasing levels of ISR classiﬁcation (0%, tiple logistic regression model to identify independent pre-0%, 27.3%, and 58.8% for types I to IV, respectively; 2 dictors of TLR. The only variables that independentlytrend, 29.4; P .001). Modalities used to treat ISR predicted TLR after CAS were a worsening pattern of ISRincluded balloon angioplasty, stenting, and cutting balloon according to our proposed ultrasound classiﬁcation (oddsangioplasty alone or in conjunction with stenting. Proce- ratio, 5.1; P .003) and the presence of diabetes (oddsdural success was achieved in all these cases, without evi- ratio, 9.7; P .04). Coronary artery disease, neurologicdence of any abrupt arterial closure or neurologic events. symptoms status, recurrent ISR and primary atherosclerosisEndovascular treatment of ISR afforded similar percentage etiologies, stent type, and stent number were not signiﬁ-diameter residual stenoses in all instances and was not cant predictors of TLR in this model.inﬂuenced by ISR class (Table III). Quantitative angiography vs B-mode imaging DISCUSSIONresults. Twenty-eight pairs of quantitative angiographic In this study we have described for the ﬁrst time, to ourand B-mode ultrasound measurements were available for knowledge, the various anatomic patterns of ISR observedcomparative analysis of the geographic distribution of the after carotid stenting. We have proposed a classiﬁcation ofISR lesions. The quantitative angiographic results veriﬁed these patterns that uses B-mode ultrasound imaging. The
JOURNAL OF VASCULAR SURGERY838 Lal et al November 2007scheme depends on the length and the geographic location ISR lesions (76.2%, type II, Table II) occurred in patientsof the intimal hyperplasia response in relation to the stent. undergoing CAS for primary atherosclerotic lesions (PThe B-mode deﬁnition of these patterns correlated with .02). Conversely, there was a trend towards fewer intrastentangiographic assessment, conﬁrming that transcutaneous ISR lesions contributed by patients undergoing CAS forultrasound imaging allowed accurate recognition of the post-CEA restenosis. To our knowledge, this is the ﬁrstpatterns of ISR occurring after CAS. observation that ISR patterns may differ according to the The proposed classiﬁcation (Fig 1) is noninvasive and etiology of the primary lesion being treated in the carotidcan be conveniently applied during each follow-up exami- artery. We have previously reported that stenting of thenation within a few minutes. It uses straight-forward B- carotid artery alters arterial wall biomechanical and hemo-mode imaging with power Doppler to outline the intimal dynamic properties.4 It is possible that stenting alters wallhyperplastic lesions, with length measurements performed properties differently in patients with calciﬁed atheroscle-on-screen using standard software provided on most cur- rotic lesions compared with more compliant ﬁbrotic post-rent ultrasound machines. Results can be printed and saved CEA restenotic lesions, thereby inducing differing patternsfor future comparisons during follow-up. The classiﬁcation of ISR.incorporates prior observations that geographic location On univariate analysis, the type of stent used for CASand lesion length are important measures of the severity of was also observed to inﬂuence the pattern of ISR (P .03,the intimal hyperplastic response to coronary stenting.14 Table II). Intrastent patterns of ISR (both focal and diffuse,We observed that the higher level pattern (diffuse prolifer- types II and III) occurred more often in patients treatedative, type IV) of ISR after CAS predicted subsequent TLR. with the Acculink stent compared with the WallStent. WeTherefore, the intimal hyperplastic response was most se- believe this is the ﬁrst observation that ISR patterns mayvere in patients who presented with the higher level of the vary according to the type of stent deployed in the carotidclassiﬁcation (type IV). We infer that the classiﬁcation artery. The results will require substantiation with a largeradequately captures the magnitude of the intimal hyper- number of patients. Stent biomechanical properties varyplastic response to CAS. according to their material, geometric design, and dimen- In a previous study, we reported that ISR occurs in a sions before and after deployment. These factors may in-signiﬁcant proportion of patients after CAS.5 Although duce variable changes in carotid arterial wall biomechan-most lesions were moderate in severity (40% to 79% steno- ics,22 thereby inﬂuencing ISR patterns. Findings from thesis), 6.4% were hemodynamically signiﬁcant ( 80% steno- current investigation may therefore impact future stentsis) and required reintervention. There is currently no way designs and material selection.to predict which of the low-grade or moderate-grade le- Despite optimal endovascular treatment with similarsions will progress to need reintervention. The present ﬁnal diameter stenosis, some individuals had an enhancedinvestigation demonstrates that a classiﬁcation of ISR pat- intimal hyperplastic response to carotid stenting. As stated,terns can independently predict the development of high- univariate analysis demonstrated that several factors couldgrade ISR necessitating reintervention. inﬂuence the magnitude of the intimal hyperplastic re- The only other independent predictor was diabetes, sponse and subsequent need for reintervention. These in-which is a well-known predictor of early and aggressive cluded the pattern of ISR after CAS, diabetes, prior ISR,intimal hyperplasia and ISR after coronary stenting.14,18 the etiology of the original lesion, and the type of stent usedOne report has observed an increased incidence of ISR in (Tables I and II). On multivariate analysis, however, thediabetic patients undergoing carotid stenting.19 However, pattern of ISR, reﬂecting the severity of the intimal hyper-the relationship between diabetes and the need for repeat plastic response to injury, independently predicted futurecarotid revascularization was not evaluated. Our study con- target vessel failure (odds ratio, 5.1; P .003). Prior ISRﬁrms that diabetes is associated with severe ISR (type IV, did not independently predict subsequent TLR. This ob-Table I) and that it is an independent predictor of target servation is different from ﬁndings in the coronary artery.18vessel failure and subsequent reintervention. Because prior ISR does result in more severe ISR after CAS, Prior ISR has been hypothesized to predict future we infer that the pattern of ISR, inﬂuenced by severalsevere recurrent ISR,5 but this has been refuted by oth- mechanisms, determines the risk for target vessel failure anders.20 Our study provides evidence that prior ISR predis- TLR in the carotid artery.poses to severe recurrent ISR (type IV, Table II). The The proposed classiﬁcation will facilitate the identiﬁca-reason for this exaggerated intimal hyperplastic response to tion of patients with severe patterns of ISR (type IV)a reintervention is unknown. In the laboratory, a severe noninvasively by ultrasound imaging. This will enable earlyintimal hyperplastic response can, however, be reproduc- selection of these patients for aggressive monitoring oribly stimulated in animal models by inducing vascular additional therapy in conjunction with stenting. Endovas-injury.21 The continuing presence of an intravascular stent cular treatment was successfully achieved without compli-may afford a similar injury stimulus for intimal hyperplasia cations in all instances of reintervention for high-gradein patients. ( 80%) ISR (Table III). We have previously reported that The most frequently occurring pattern of ISR in our post-CAS ISR is a neointimal hyperplastic lesion that is notcohort was the focal end-stent type (type I, Table I). On associated with the same risk of atheroembolic complica-univariate analysis, we observed that most of the intrastent tions as in primary atherosclerotic lesions.5 The multiple
JOURNAL OF VASCULAR SURGERYVolume 46, Number 5 Lal et al 839modalities used (plain/cutting balloon angioplasty, pri- for intensive monitoring and treatment. By providing amary stenting or a combination of these) indicate an ab- standardized method of describing restenotic lesions, it willsence of consensus on the optimal method of treatment. also facilitate further investigations into adjunctive treat-Intravascular radiation23 and local24 or systemic25 pharma- ments for ISR and improved stent design.cologic agents are under active investigation in high-riskcoronary ISR patients and may prove beneﬁcial in their AUTHOR CONTRIBUTIONStreatment. Early and appropriate identiﬁcation and treat- Conception and design: BLment of these high-risk ISR patients using our ultrasound Analysis and interpretation: BL, EK, RHclassiﬁcation may improve cost-effective patient manage- Data collection: BL, EK, SC, IK, RHment and help develop novel revascularization strategies. Writing the article: BL, RH Limitations. This retrospective analysis is subject to Critical revision of the article: BL, EK, SC, IK, RHthe limitations related to such an investigation. Data were Final approval of the article: BL, EK, SC, IK, RHretrieved from our CAS Quality Assurance Database. The Statistical analysis: BLdatabase is updated prospectively and incorporates the Obtained funding: BL, RHsame information for all carotid stenosis patients undergo- Overall responsibility: BLing endovascular interventions, regardless of clinical indi-cations and outcomes. Because selective carotid angiogra- REFERENCESphy is associated with a risk of atheroembolic stroke,26 thismodality was not used for routine follow-up. Duplex ultra- 1. Hobson RW 2nd, Goldstein JE, Jamil Z, Lee BC, Padberg FT Jr, Hanna AK, et al. Carotid restenosis: operative and endovascular man-sonography is readily available at our certiﬁed vascular agement. J Vasc Surg 1999;29:228-35; discussion 235-8.laboratory. 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