- Email: [email protected]
Octogenarians are not at Increased Risk for Periprocedural Stroke following Carotid Artery Stenting
Clinical Research Octogenarians are not at Increased Risk for Periprocedural Stroke following Carotid Artery Stenting J. Michael Bacharach,1,2 David P. Slovut,3,4 Joseph Ricotta,5 and Timothy M. Sullivan,6 Sioux Falls, South Dakota; Salem and Boston, Massachusetts; Rochester and Minneapolis, Minnesota
Background: We analyzed the risk of adverse events following carotid angioplasty and stenting (CAS) in patients <80 years (group I) compared with those 80 years of age (group II). Methods: Prospective data from 224 patients who underwent 235 consecutive CAS procedures at three participating institutions were reviewed retrospectively. All subjects were enrolled in Food and Drug Administrationeapproved clinical trials of CAS in high-risk patients or in institutional protocols. Procedural details and angiographic morphology were reviewed in all cases. All patients underwent independent neurological evaluation at 24 hr and 30 days following CAS. Results: Mean age was 69.9 years in the younger cohort and 83.5 years in the older group. Embolic protection devices were successfully deployed in 97.5% of cases in group I compared with 98.7% in group II ( p ¼ nonsignificant [NS]). Procedural success, defined as <30% residual stenosis after CAS, was achieved in all cases. Mean hospital stay was similar in the two groups. Transient ischemia attacks occurred in 1.9% in group I and 1.3% in group II ( p ¼ NS). Within 30 days of CAS, the risk of minor or major stroke ( p ¼ NS) as well as the composite risk of stroke (minor or major) and death was 2.5% in group I and 3.8% in group II ( p ¼ NS). Multivariate logistic regression analysis showed that absence of hypertension (odds ratioi [OR] ¼ 0.38, p ¼ 0.0352) and chronic renal insufficiency (OR ¼ 2.62, p ¼ 0.0238) were significant predictors of the composite end point of stroke and all-cause mortality. Kaplan-Meier analysis revealed that survival and freedom from the combined end point of stroke and all-cause mortality were similar for patients in groups I and II. Conclusion: Octogenarians are not at increased risk of periprocedural adverse events following CAS compared to younger patients. Exclusion of high-risk patients from CAS based on age alone is unjustified.
INTRODUCTION Numerous randomized controlled trials and registry series have established carotid artery stenting (CAS) as a reasonable stroke-prevention strategy in patients considered at increased risk for carotid
1 Department of Cardiology, Heart Hospital of South Dakota, Sioux Falls, SD. 2
Department of Medicine, University of South Dakota, Sioux Falls,
SD. 3 Departments of Cardiology and Vascular Medicine, North Shore Medical Center, Salem, MA. 4
Department of Vascular Medicine, Massachusetts General Hospital, Boston, MA. 5
Department of Surgery, Mayo Clinic, Rochester, MN.
endarterectomy (CEA).1-5 CEA remains the treatment of choice for ‘‘good-risk’’ patients with highgrade carotid artery stenosis, as documented by the North American Symptomatic Carotid Endarterectom Trial (NASCET) and Asymptomatic Carotid Atherosclerosis Study (ACAS); however, these
6 Department of Vascular and Endovascular Surgery, Minneapolis Heart Institute, Minneapolis, MN.
Correspondence to: J. Michael Bacharach, MD, MPH, Heart Hospital of South Dakota, 4500 West 69th Street, Sioux Falls, SD 57108, USA, E-mail: [email protected] Ann Vasc Surg 2010; 24: 153-159 DOI: 10.1016/j.avsg.2009.05.010 Ó Annals of Vascular Surgery Inc. Published online: September 14, 2009
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seminal trials, which compared CEA with medical therapy, excluded octogenarians.6,7 Subsequent CEA trials have offered mixed conclusions on the safety of CEA in the elderly. Retrospective analysis of 3,092 CEAs in northern New England revealed a nearly threefold increase in the risk of perioperative stroke for patients over the age of 70.8 Other large academic series have shown that age is not associated with an increased risk of stroke.9-12 Because of a perceived increased adverse event rate in the elderly, interest developed in offering CAS to this group. Initial CAS trials performed without the use of distal embolic protection yielded unacceptably high rates of stroke and death.13,14 Several subsequent studies suggested that even with use of distal embolic protection, octogenarians undergoing CAS remain at significantly higher risk for periprocedural complications.15-17 Lead-in data from the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) demonstrated 30-day stroke rates in octogenarians of 12.1% compared to 4.0% in the nonoctogenarian group.15 The influence of advanced age on the safety of carotid artery revascularization remains controversial. Based on these studies, it has been suggested by some that octogenarians should not be treated with CAS. The purpose of this study was to determine whether outcomes following CAS in octogenarians were equivalent to those in patients younger than 80 years.
METHODS Two hundred and thirty-four consecutive patients underwent CAS from March 2001 to April 2006 at three institutions as part of multicenter registry studies, randomized trials, or institutional protocols. Patients were included if they were asymptomatic with angiographic carotid stenosis 80% or symptomatic with 50% carotid stenosis. Patients were considered symptomatic if they experienced transient ischemic attacks (TIAs), amaurosis fugax, or strokes with clinically correlated lateralizing symptoms within 90 days of carotid stenting. Data for each CAS procedure were prospectively collected via institutional registries and reviewed retrospectively. Each of the three enrolling centers obtained approval from its respective institutional review board for human subject investigation. Informed consent was obtained from all patients. Carotid stenting was performed under local anesthesia according to standard protocols within each institution. Cerebral embolic protection devices were routinely utilized. The choice of protection device and stent was in accordance with the trial
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protocol in which the patient was enrolled or the individual operator’s preference (Appendix 1). Stenosis severity prior to and following stent placement was determined using NASCET criteria.6 Patients received orally administered aspirin (81 or 325 mg daily) indefinitely and clopidogrel within 1 week of the procedure, followed by 75 mg daily for 4 weeks. Following CAS, patients were monitored closely during an overnight hospital stay. Cardiac enzymes were obtained in all patients. All patients underwent independent neurological evaluation utilizing the National Institutes of Health Stroke Scale (NIHSS) prior to and 24 hr and 30 days following the procedure. A carotid duplex was obtained at 4 weeks to document stent patency. Data Collection Patient demographics and comorbidities were recorded. Hypertension was defined according to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines.18 Hyperlipidemia was defined according to National Cholesterol Education Program Adult Treatment Panel III guidelines.19 Aortic arch elongation was defined by arch vessels arising from the top of the arch (type I), between the parallel planes delineated by the outer and inner curves of the arch (type II), and caudal to the inner surface of the arch or originating from the ascending aorta (type III).20 Primary end points included TIA, minor cerebrovascular accident (CVA), major CVA, in-hospital myocardial infarction, and death. TIA was defined as any reversible neurological deficit occurring after the procedure and lasting <24 hr; minor CVA was defined as any new neurological deficit, either ocular or cerebral, that persisted for >24 hr and increased the NIHSS by 3 points; major CVA was defined as any new neurological deficit, either ocular or cerebral, that persisted >24 hr and increased the NIHSS by >3 points; fatal stroke was defined as death attributed to any ischemic or hemorrhagic stroke. Myocardial infarction was present if there were new electrocardiographic changes (new Q wave in two or more leads), an elevation in CK-MB (isoenzyme of creatine kinase with muscle and brain subunits) more than twice normal, or an abnormal troponin I. Access site complications included hematoma, arteriovenous fistula, pseudoaneurysm requiring treatment, or hemorrhage requiring blood transfusion. Statistical Analysis Pooled data were divided into age <80 and age 80. Results of continuous variables are expressed as the
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mean ± standard deviation. Categorical data were compared using chi-squared analysis. Fisher’s exact test was used when the predicted contingency table cell values were <5. Continuous variables were evaluated using analysis of variance or the MannWhitney/Wilcoxon two-sample test, as appropriate. Bivariate logistic regression analysis was performed to examine the relationship between the composite dependent variable any stroke and all-cause mortality and the following independent variables: age, gender, presence of coronary artery stenosis >70% in two vessels, history of congestive heart failure, ejection fraction, presence of hypertension, dyslipidemia, diabetes mellitus, peripheral vascular disease, smoking history, chronic obstructive pulmonary disease (COPD), and serum creatinine. Significant variables from univariate analysis were examined using multivariate logistic regression. Survival was determined using Kaplan-Meier lifetable analysis. Censored data for each analysis consisted of patients who died for any reason. All analyses were performed using Epi Info, version 3.3.2 (Centers for Disease Control, Atlanta, GA). Statistical significance was assumed at p < 0.05.
RESULTS There were 152 patients in the <80 age group (group I) and 79 patients in the 80 age group (group II). Five patients in group I and two in group II were excluded because they lacked 30-day followup information. Thus, the analysis includes 147 patients who underwent 157 carotid stent procedures in group I and 77 patients who underwent 78 procedures in group II. Baseline demographic characteristics of the two groups are summarized in Table I. Compared with patients in group II, the younger cohort had a greater percentage of smokers and of those with COPD and angina. A greater percentage of patients in group I had undergone ipsilateral CEA (38.9% vs. 10.3%, p < 0.0001) or had received radiation to the neck (8.9% vs. 2.6%, p ¼ 0.054). Table II summarizes anatomic and procedural data. Compared with patients in group I, octogenarians were more likely to have elongation of the aortic arch. Lesion characteristics including length and degree of calcium were similar between the groups. Embolic protection devices were placed successfully in 97.5% of group I and 98.7% of group II patients ( p ¼ nonsignificant [NS]). Filter retrieval was successful in 100% of cases. Procedural success, defined as residual stenosis < 30% by visual estimate following stenting, was achieved in all patients. The mean hospital stay was 1.4 ± 1.9 days
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Table I. Baseline demographic factors <80 (n ¼ 157) (%)
Demographics Age Male gender Risk factors Coronary artery disease CCS3 or 4 Congestive heart failure Ejection fraction Hypertension Hyperlipidemia Diabetes mellitus Peripheral vascular disease Tobacco use COPD Serum creatinine Anatomic risk factors Ipsilateral CEA Contralateral occlusion Neck radiation Neck dissection High lesion Baseline medical therapy Antiplatelet ACE I ß-blocker Antilipid Presentation Asymptomatic Amaurosis TIA Stroke
80 (n ¼ 78) (%)
p
69.9 ± 7.3 83.5 ± 2.7 <0.0001 110 (70.1) 56 (71.8) 0.784 105 (66.9) 54 (70.1)
0.616
7 (4.6) 0 (0) 30 (19.7) 17 (21.8)
0.056 0.714
52 ± 17 136 (86.6) 134 (85.9) 47 (30.1) 58 (37.4)
50 ± 15 60 (78.9) 59 (76.6) 21 (26.0) 27 (37.5)
121 (77.1) 38 (49.4) 32 (21.8) 8 (11.1) 1.3 ± 0.7 1.3 ± 0.7
0.696 0.138 0.077 0.510 0.991 <0.0001 0.055 0.944
61 (38.9) 20 (12.7)
8 (10.3) 6 (7.7)
<0.0001 0.245
14 (8.9) 14 (8.9) 11 (7.1)
2 (2.6) 3 (3.8) 2 (2.6)
0.054 0.124 0.131
157 78 94 113
(100) (49.7) (59.9) (72.0)
77 31 41 47
(98.7) (39.7) (51.3) (60.3)
0.332 0.150 0.210 0.069
120 6 17 13
(76.4) 62 (79.5) (3.8) 3 (3.8) (11.0) 8 (10.3) (8.3) 2 (2.6)
0.599 0.626 0.868 0.074
CCS3or4, Canadian Cardiovascular class 3 or 4 angina; COPD, chronic obstructive pulmonary disease; CEA, carotid endarterectomy; TIA, transient ischemic attack; ACE, angiotensin-converting enzyme.
(range 1e20) in group I and 1.3 ± 0.9 days (range 1e7) in group II ( p ¼ NS). By the second postprocedure day, 93.6% of the younger cohort and 94.8% of patients 80 old were discharged home. Periprocedural neurological events and mortality at 30 days were similar between the groups (Table III). None of the patients in either group suffered a myocardial infarction within 30 days of CAS. There was no significant difference in the overall 30-day stroke rate between symptomatic and asymptomatic patients. The incidence of TIA was slightly higher in the octogenarian group, but
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Table II. Anatomic and procedural data
Lesion length (mm) Lesion calciuma Aortic arch type I II III Thrombus
<80 (n ¼ 157) (%)
80 (n ¼ 78) (%)
p
15.2 ± 7.0 28 (18.7)
15.2 ± 9.2 15 (20.0)
0.995 0.810
92 57 0 2
38 36 2 2
0.047
(61.7) (38.3) (0) (1.3)
(50.0) (47.4) (2.6) (2.6)
0.405
a
Percentage of patients with moderate or severe lesion calcification.
Table III. 30-day outcome <80 (n ¼ 157) 80 (n ¼ 78) (%) (%) p
TIA CVA (minor) CVA (major) CVA (fatal) Death CVA/death Access site complication Hemorrhage Acute renal failure Myocardial infarction Congestive heart failure
3 1 2 1 1 4 5 5 2 0 0
(1.9) (0.6) (1.3) (0.6) (0.6) (2.5) (3.2) (3.2) (1.3)
1 2 1 0 0 3 5 1 0 0 0
(1.3) (2.6) (1.3) (0.0) (0.0) (3.8) (6.4) (1.3) (0.0)
0.595 0.256 0.704 0.668 0.668 0.426 0.249 0.351 0.445 NS NS
TIA, transient ischemic attack; CVA, cerebral vascular accident.
the difference did not reach statistical significance. Univariate analysis demonstrated a significant relationship between absence of hypertension ( p ¼ 0.0276) and serum creatinine >1.4 ( p ¼ 0.0176) and the combined end point of stroke and all-cause mortality. On multivariate analysis, both absence of hypertension (odds ratio [OR] ¼ 0.38, p ¼ 0.0352) and chronic renal insufficiency (OR ¼ 2.62, p ¼ 0.0238) remained significant predictors of the composite end point of stroke and all-cause mortality. Mean follow-up was 17.9 ± 14.8 months (range 1e72). Kaplan-Meier analysis revealed that survival (Fig. 1) and freedom from the combined end point of stroke and all-cause mortality (Fig. 2) were similar for patients <80 and those 80.
DISCUSSION Our data suggest that carotid stenting in octogenarians is not associated with an increased risk of adverse events at 30 days or at mid-term follow-up. In elderly patients, carotid artery revascularizationdwhether by surgery or stentingdremains
controversial. Many large, single-center academic series have reported stroke and death rates of 2.2e 2.8% in octogenarians following CEA.9-11 Others have identified advanced age as an independent predictor of stroke following CEA. Goodney et al.,8 in a series of 3,092 primary CEAs performed at 11 hospitals in northern New England, found that age >70 years was associated with perioperative stroke. In some single-center surgical series, patients did not undergo independent neurological evaluation during the postoperative period, and as such, actual event rates may have been higher than were reported.21 The risk of periprocedural stroke and death following endovascular carotid revascularization also varies across studies. A number of small series, registries, and lead-in data from the CREST trial suggest that there is a marked difference in periprocedural and 30-day stroke rates in octogenarians versus younger patients.15,17,22 Stanziale and colleagues16 found an 8.0% stroke rate in octogenarians compared with a 2.7% in younger patients. Kastrup et al.17 compared CAS with CEA and found a higher rate of minor stroke, but not major stroke, in octogenarians versus younger patients. Theiss et al.23 reported a subgroup analysis of the Pro-CAS data on numerous variables that were predictors of peri-interventional stroke or death. While the rate of events in the >80 year group was higher (6.3% compared with 3.8%) than in the 70e79 year group, the difference did not reach statistical significance. The most important variable was center experience: Centers that performed more than 50 interventions per year had a lower event rate than lower-volume institutions. This study underscores the importance of experience both with the procedure and with patient selection. The authors concluded that dedicated training and strict credentialing rules for CAS were vital. Several explanationsdsymptomatic status, anatomic factors, hemodynamic instability, and operator experiencedhave been offered to account for the increased stroke rates in octogenarians following CAS. Investigators for the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausa¨rzte (ALKK) Carotid Artery Stent registry noted a difference in stroke rates in symptomatic patients of 7.1% in patients >80 compared to 3.9% in those <80 years old.22 In asymptomatic patients the difference was 3.4% vs. 2.6%, respectively. The authors suggested that the larger number of symptomatic patients in the >80 year group accounted for the increased stroke rate. In both the present series and the CREST lead-in population, no association was observed between symptomatic status and the composite variable stroke and all-cause mortality.15
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Fig. 1. Kaplan-Meier plot depicting survival following CAS. Solid line, group I (age <80); dashed line, group II.
Fig. 2. Kaplan-Meier plot showing freedom from the combined end point of stroke and death following CAS. Solid line, group I (age <80); dashed line, group II.
Certain anatomic features, such as the carotid string sign, extensive calcification, and severe vessel tortuosity, place patients, regardless of age, at greater risk for adverse outcomes. Patients >80 years old often have more complex aortic arch morphology, arch calcification, and common carotid and internal carotid artery tortuosity than younger patients,
which may lead to poorer outcomes.20,24 These features can make CAS more difficult to perform and may contribute to longer procedure times, a greater percentage of aborted procedures, and increased residual stenosis after CAS observed in octogenarians compared with their younger counterparts.22 However, these variables are not unique
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to the elderly; our data suggest that chronological age alone is an inadequate discriminator of CAS risk. Profound bradycardia as well as symptomatic hypotension or hypertension are seen more commonly in patients 75 than in younger patients. In a series by Groschel et al.,25 age 75 years predicted postprocedure hemodynamic instability (4.3% in patients <75 years vs. 10.4% in patients 75, p < 0.05) as well as the occurrence of severe medical complications such as myocardial infarction and TIAs (3.5% in patients <75 vs. 13.5% in patients 75, p < 0.05). Narrative summaries from octogenarians in the CREST leadin phase specifically noted severe tortuosity (>90 degrees) in two patients that did not allow embolic protection to be placed and hypotension and bradycardia in seven of 10 patients, all of whom suffered central nervous system events.15 Hemodynamic instability during CAS may have contributed to the higher incidence of neurological complications among octogenarians. The extent to which operator experience and patient selection influence outcomes in elderly patients is difficult to quantify. The patients in the present study were selected based on established high-risk criteria first proposed by the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial and subsequently adopted by the other high-risk trials and registries. Beyond these basic inclusion and exclusion criteria it is impossible to compare subtle operator selection bias that may have influenced patient selection for CAS. Moreover, experienced interventionalists are more likely to recognize anatomy that makes a CAS procedure treacherous and to make adjustments to minimize procedural risk than less experienced operators. Operators at all three centers included in the present study are experienced vascular interventionalists with extensive CAS experience. This may have allowed for better patient selection and exclusion of patients felt to be at inordinately high risk for stroke following CAS based on anatomic factors. The data presented herein suggest that CAS in octogenarians is not associated with an increased risk of adverse events at 30 days and at mean follow-up of 1.5 years. Our results are consistent with those Longo and colleagues,26 who found similar event rates in all age groups following CAS, with no increased risk in octogenarians. We found that renal insufficiency correlated with increased risk of the composite of any stroke and all-cause mortality. This finding is in agreement with other series that showed that renal dysfunction is associated with increased mortality following carotid
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revascularization.27-29 The relationship between absence of hypertension and the composite outcome of stroke or death remains troubling. The association was driven by all-cause mortality, not stroke, which was similar in patients with and without hypertension. We acknowledge certain study limitations. This study was a retrospective review and, compared to many other studies, represents a relatively small number of patients. Additionally, elderly patients who were not deemed appropriate for CAS were excluded and either underwent CEA or medical therapy. Patient selection was dependent on the operator, and subtle bias was not controlled for. Available data and follow-up were not designed to specifically assess factors that could have contributed to our observed outcomes compared to other studies. Factors of patient selection beyond basic high-risk criteria, specifics of procedural technique, the overall health of our older population, and racial or genetic factors may account for the difference in our observed experience. Studies designed and powered to address some of these specific issues and to further evaluate the influence of age on outcomes will be required before a definitive assessment of risk can be determined.
CONCLUSION CAS in high-risk patients can be performed safely by experienced operators. Octogenarians are not at increased risk of periprocedural adverse events following CAS compared to younger patients. Exclusion of high-risk patients from CAS based on age alone is unjustified.
The authors thank Patty Eisenbraun, RN; Robin Farley, RN; and Teresa Harwood, RN, for assistance in compiling data for this study.
APPENDIX 1 Trials represented in this study: ACT I - Asymptomatic Carotid Stenosis, Stenting Versus Endarterectomy Trial; ARCHeR ACCULINK for Revascularization of Carotids in High Risk Patients; CAPTURE - Carotid Acculink/Accunet Post Approval Trial to Uncover Rare Events (Post Market); CARESS - Carotid Revascularization with Endarterectomy or Stenting Systems; CHOICE - Carotid Stenting for High Survival-Risk Patient, Evaluating Outcomes through the Collection of Clinical
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Evidence (Post Market); CREATE-Feasability, CREATE-Pivotal, and CREATE-Spider Rx - Carotid Revascularization with ev3 Arterial Technology Evolution; EPIC US Feasability Study and EPIC US Pivotal Study - Evaluating the Use of Fibernet Embolic Protection System in Carotid Artery Stenting; MAVErIC II and MAVErIC III - Evaluation of Medtronic AVE Self Expanding Carotid Stent System with Distal Protection in the Treatment of Carotid Stenosis; PRIAMUS - Proximal Flow Blockage Cerebral Protection During Carotid Stenting; SAPPHIRE WW - Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy World Wide (Post Market); VIVA - The Bard Vivexx Carotid Revascularization Trial. REFERENCES 1. Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotidartery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004;351:1493-1501. 2. Carotid Revascularization Using Endarterectomy or Stenting Systems (CaRESS) phase I clinical trial: 1-year results. J Vasc Surg 2005;42:213-219. 3. Safian RD, Bacharach JM, Ansel GM, Criado FJ. Carotid stenting with a new system for distal embolic protection and stenting in high-risk patients: the Carotid Revascularization with ev3 Arterial Technology Evolution (CREATE) feasibility trial. Catheter Cardiovasc Interv 2004;63:1-6. 4. Gray WA, Hopkins LN, Yadav S, et al. Protected carotid stenting in high-surgical-risk patients: the ARCHeR results. J Vasc Surg 2006;44:258-268. 5. Gray WA, Yadav JS, Verta P, et al. The CAPTURE registry: results of carotid stenting with embolic protection in the post approval setting. Catheter Cardiovasc Interv 2007;69:341-348. 6. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445-453. 7. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995;273:1421-1428. 8. Goodney PP, Likosky DS, Cronenwett JL. Factors associated with stroke or death after carotid endarterectomy in northern New England. J Vasc Surg 2008;48:1139-1145. 9. O’Hara PJ, Hertzer NR, Mascha EJ, Beven EG, Krajewski LP, Sullivan TM. Carotid endarterectomy in octogenarians: early results and late outcome. J Vasc Surg 1998;27:860-870. 10. Perler BA, Dardik A, Burleyson GP, Gordon TA, Williams GM. Influence of age and hospital volume on the results of carotid endarterectomy: a statewide analysis of 9918 cases. J Vasc Surg 1998;27:25-31. 11. Mozes G, Sullivan TM, Torres-Russotto DR, et al. Carotid endarterectomy in SAPPHIRE-eligible high-risk patients: implications for selecting patients for carotid angioplasty and stenting. J Vasc Surg 2004;39:958-965. 12. Pruner G, Castellano R, Jannello AM, et al. Carotid endarterectomy in the octogenarian: outcomes of 345 procedures performed from 1995e2000. Cardiovasc Surg 2003;11: 105-112.
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13. Chastain HD, 2nd, Gomez CR, Iyer S, et al. Influence of age upon complications of carotid artery stenting. UAB Neurovascular Angioplasty Team. J Endovasc Surg 1999;6: 217-222. 14. Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lancet 2001;357:1729-1737. 15. Hobson RW, 2nd, Howard VJ, Roubin GS, et al. Carotid artery stenting is associated with increased complications in octogenarians: 30-day stroke and death rates in the CREST lead-in phase. J Vasc Surg 2004;40:1106-1111. 16. Stanziale SF, Marone LK, Boules TN, et al. Carotid artery stenting in octogenarians is associated with increased adverse outcomes. J Vasc Surg 2006;43:297-304. 17. Kastrup A, Schulz JB, Raygrotzki S, Groschel K, Ernemann U. Comparison of angioplasty and stenting with cerebral protection versus endarterectomy for treatment of internal carotid artery stenosis in elderly patients. J Vasc Surg 2004;40:945-951. 18. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572. 19. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-239. 20. Lin SC, Trocciola SM, Rhee J, et al. Analysis of anatomic factors and age in patients undergoing carotid angioplasty and stenting. Ann Vasc Surg 2005;19:798-804. 21. Rothwell PM, Slattery J, Warlow CP. A systematic review of the risks of stroke and death due to endarterectomy for symptomatic carotid stenosis. Stroke 1996;27: 260-265. 22. Zahn R, Ischinger T, Hochadel M, et al. Carotid artery stenting in octogenarians: results from the ALKK Carotid Artery Stent (CAS) Registry. Eur Heart J 2007;28:370-375. 23. Theiss W, Hermanek P, Mathias K, et al. Predictors of death and stroke after carotid angioplasty and stenting: a subgroup analysis of the Pro-CAS data. Stroke 2008;39: 2325-2330. 24. Bazan HA, Pradhan S, Mojibian H, Kyriakides T, Dardik A. Increased aortic arch calcification in patients older than 75 years: implications for carotid artery stenting in elderly patients. J Vasc Surg 2007;46:841-845. 25. Groschel K, Ernemann U, Riecker A, Schmidt F, Terborg C, Kastrup A. Incidence and risk factors for medical complications after carotid artery stenting. J Vasc Surg 2005;42: 1101-1107. 26. Longo GM, Kibbe MR, Eskandari MK. Carotid artery stenting in octogenarians: is it too risky? Ann Vasc Surg 2005;19:812-816. 27. Debing E, Van den Brande P. Chronic renal insufficiency and risk of early mortality in patients undergoing carotid endarterectomy. Ann Vasc Surg 2006;20:609-613. 28. Ayerdi J, Sampson LN, Deshmukh N, Farid A, Gupta SK. Carotid endarterectomy in patients with renal insufficiency: should selection criteria be different in patients with renal insufficiency? Vasc Surg 2001;35:429-435. 29. Ascher E, Marks NA, Schutzer RW, Hingorani AP. Carotid endarterectomy in patients with chronic renal insufficiency: a recent series of 184 cases. J Vasc Surg 2005;41: 24-29.
Background: We analyzed the risk of adverse events following carotid angioplasty and stenting (CAS) in patients <80 years (group I) compared with those 80 years of age (group II). Methods: Prospective data from 224 patients who underwent 235 consecutive CAS procedures at three participating institutions were reviewed retrospectively. All subjects were enrolled in Food and Drug Administrationeapproved clinical trials of CAS in high-risk patients or in institutional protocols. Procedural details and angiographic morphology were reviewed in all cases. All patients underwent independent neurological evaluation at 24 hr and 30 days following CAS. Results: Mean age was 69.9 years in the younger cohort and 83.5 years in the older group. Embolic protection devices were successfully deployed in 97.5% of cases in group I compared with 98.7% in group II ( p ¼ nonsignificant [NS]). Procedural success, defined as <30% residual stenosis after CAS, was achieved in all cases. Mean hospital stay was similar in the two groups. Transient ischemia attacks occurred in 1.9% in group I and 1.3% in group II ( p ¼ NS). Within 30 days of CAS, the risk of minor or major stroke ( p ¼ NS) as well as the composite risk of stroke (minor or major) and death was 2.5% in group I and 3.8% in group II ( p ¼ NS). Multivariate logistic regression analysis showed that absence of hypertension (odds ratioi [OR] ¼ 0.38, p ¼ 0.0352) and chronic renal insufficiency (OR ¼ 2.62, p ¼ 0.0238) were significant predictors of the composite end point of stroke and all-cause mortality. Kaplan-Meier analysis revealed that survival and freedom from the combined end point of stroke and all-cause mortality were similar for patients in groups I and II. Conclusion: Octogenarians are not at increased risk of periprocedural adverse events following CAS compared to younger patients. Exclusion of high-risk patients from CAS based on age alone is unjustified.
INTRODUCTION Numerous randomized controlled trials and registry series have established carotid artery stenting (CAS) as a reasonable stroke-prevention strategy in patients considered at increased risk for carotid
1 Department of Cardiology, Heart Hospital of South Dakota, Sioux Falls, SD. 2
Department of Medicine, University of South Dakota, Sioux Falls,
SD. 3 Departments of Cardiology and Vascular Medicine, North Shore Medical Center, Salem, MA. 4
Department of Vascular Medicine, Massachusetts General Hospital, Boston, MA. 5
Department of Surgery, Mayo Clinic, Rochester, MN.
endarterectomy (CEA).1-5 CEA remains the treatment of choice for ‘‘good-risk’’ patients with highgrade carotid artery stenosis, as documented by the North American Symptomatic Carotid Endarterectom Trial (NASCET) and Asymptomatic Carotid Atherosclerosis Study (ACAS); however, these
6 Department of Vascular and Endovascular Surgery, Minneapolis Heart Institute, Minneapolis, MN.
Correspondence to: J. Michael Bacharach, MD, MPH, Heart Hospital of South Dakota, 4500 West 69th Street, Sioux Falls, SD 57108, USA, E-mail: [email protected] Ann Vasc Surg 2010; 24: 153-159 DOI: 10.1016/j.avsg.2009.05.010 Ó Annals of Vascular Surgery Inc. Published online: September 14, 2009
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seminal trials, which compared CEA with medical therapy, excluded octogenarians.6,7 Subsequent CEA trials have offered mixed conclusions on the safety of CEA in the elderly. Retrospective analysis of 3,092 CEAs in northern New England revealed a nearly threefold increase in the risk of perioperative stroke for patients over the age of 70.8 Other large academic series have shown that age is not associated with an increased risk of stroke.9-12 Because of a perceived increased adverse event rate in the elderly, interest developed in offering CAS to this group. Initial CAS trials performed without the use of distal embolic protection yielded unacceptably high rates of stroke and death.13,14 Several subsequent studies suggested that even with use of distal embolic protection, octogenarians undergoing CAS remain at significantly higher risk for periprocedural complications.15-17 Lead-in data from the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) demonstrated 30-day stroke rates in octogenarians of 12.1% compared to 4.0% in the nonoctogenarian group.15 The influence of advanced age on the safety of carotid artery revascularization remains controversial. Based on these studies, it has been suggested by some that octogenarians should not be treated with CAS. The purpose of this study was to determine whether outcomes following CAS in octogenarians were equivalent to those in patients younger than 80 years.
METHODS Two hundred and thirty-four consecutive patients underwent CAS from March 2001 to April 2006 at three institutions as part of multicenter registry studies, randomized trials, or institutional protocols. Patients were included if they were asymptomatic with angiographic carotid stenosis 80% or symptomatic with 50% carotid stenosis. Patients were considered symptomatic if they experienced transient ischemic attacks (TIAs), amaurosis fugax, or strokes with clinically correlated lateralizing symptoms within 90 days of carotid stenting. Data for each CAS procedure were prospectively collected via institutional registries and reviewed retrospectively. Each of the three enrolling centers obtained approval from its respective institutional review board for human subject investigation. Informed consent was obtained from all patients. Carotid stenting was performed under local anesthesia according to standard protocols within each institution. Cerebral embolic protection devices were routinely utilized. The choice of protection device and stent was in accordance with the trial
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protocol in which the patient was enrolled or the individual operator’s preference (Appendix 1). Stenosis severity prior to and following stent placement was determined using NASCET criteria.6 Patients received orally administered aspirin (81 or 325 mg daily) indefinitely and clopidogrel within 1 week of the procedure, followed by 75 mg daily for 4 weeks. Following CAS, patients were monitored closely during an overnight hospital stay. Cardiac enzymes were obtained in all patients. All patients underwent independent neurological evaluation utilizing the National Institutes of Health Stroke Scale (NIHSS) prior to and 24 hr and 30 days following the procedure. A carotid duplex was obtained at 4 weeks to document stent patency. Data Collection Patient demographics and comorbidities were recorded. Hypertension was defined according to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines.18 Hyperlipidemia was defined according to National Cholesterol Education Program Adult Treatment Panel III guidelines.19 Aortic arch elongation was defined by arch vessels arising from the top of the arch (type I), between the parallel planes delineated by the outer and inner curves of the arch (type II), and caudal to the inner surface of the arch or originating from the ascending aorta (type III).20 Primary end points included TIA, minor cerebrovascular accident (CVA), major CVA, in-hospital myocardial infarction, and death. TIA was defined as any reversible neurological deficit occurring after the procedure and lasting <24 hr; minor CVA was defined as any new neurological deficit, either ocular or cerebral, that persisted for >24 hr and increased the NIHSS by 3 points; major CVA was defined as any new neurological deficit, either ocular or cerebral, that persisted >24 hr and increased the NIHSS by >3 points; fatal stroke was defined as death attributed to any ischemic or hemorrhagic stroke. Myocardial infarction was present if there were new electrocardiographic changes (new Q wave in two or more leads), an elevation in CK-MB (isoenzyme of creatine kinase with muscle and brain subunits) more than twice normal, or an abnormal troponin I. Access site complications included hematoma, arteriovenous fistula, pseudoaneurysm requiring treatment, or hemorrhage requiring blood transfusion. Statistical Analysis Pooled data were divided into age <80 and age 80. Results of continuous variables are expressed as the
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mean ± standard deviation. Categorical data were compared using chi-squared analysis. Fisher’s exact test was used when the predicted contingency table cell values were <5. Continuous variables were evaluated using analysis of variance or the MannWhitney/Wilcoxon two-sample test, as appropriate. Bivariate logistic regression analysis was performed to examine the relationship between the composite dependent variable any stroke and all-cause mortality and the following independent variables: age, gender, presence of coronary artery stenosis >70% in two vessels, history of congestive heart failure, ejection fraction, presence of hypertension, dyslipidemia, diabetes mellitus, peripheral vascular disease, smoking history, chronic obstructive pulmonary disease (COPD), and serum creatinine. Significant variables from univariate analysis were examined using multivariate logistic regression. Survival was determined using Kaplan-Meier lifetable analysis. Censored data for each analysis consisted of patients who died for any reason. All analyses were performed using Epi Info, version 3.3.2 (Centers for Disease Control, Atlanta, GA). Statistical significance was assumed at p < 0.05.
RESULTS There were 152 patients in the <80 age group (group I) and 79 patients in the 80 age group (group II). Five patients in group I and two in group II were excluded because they lacked 30-day followup information. Thus, the analysis includes 147 patients who underwent 157 carotid stent procedures in group I and 77 patients who underwent 78 procedures in group II. Baseline demographic characteristics of the two groups are summarized in Table I. Compared with patients in group II, the younger cohort had a greater percentage of smokers and of those with COPD and angina. A greater percentage of patients in group I had undergone ipsilateral CEA (38.9% vs. 10.3%, p < 0.0001) or had received radiation to the neck (8.9% vs. 2.6%, p ¼ 0.054). Table II summarizes anatomic and procedural data. Compared with patients in group I, octogenarians were more likely to have elongation of the aortic arch. Lesion characteristics including length and degree of calcium were similar between the groups. Embolic protection devices were placed successfully in 97.5% of group I and 98.7% of group II patients ( p ¼ nonsignificant [NS]). Filter retrieval was successful in 100% of cases. Procedural success, defined as residual stenosis < 30% by visual estimate following stenting, was achieved in all patients. The mean hospital stay was 1.4 ± 1.9 days
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Table I. Baseline demographic factors <80 (n ¼ 157) (%)
Demographics Age Male gender Risk factors Coronary artery disease CCS3 or 4 Congestive heart failure Ejection fraction Hypertension Hyperlipidemia Diabetes mellitus Peripheral vascular disease Tobacco use COPD Serum creatinine Anatomic risk factors Ipsilateral CEA Contralateral occlusion Neck radiation Neck dissection High lesion Baseline medical therapy Antiplatelet ACE I ß-blocker Antilipid Presentation Asymptomatic Amaurosis TIA Stroke
80 (n ¼ 78) (%)
p
69.9 ± 7.3 83.5 ± 2.7 <0.0001 110 (70.1) 56 (71.8) 0.784 105 (66.9) 54 (70.1)
0.616
7 (4.6) 0 (0) 30 (19.7) 17 (21.8)
0.056 0.714
52 ± 17 136 (86.6) 134 (85.9) 47 (30.1) 58 (37.4)
50 ± 15 60 (78.9) 59 (76.6) 21 (26.0) 27 (37.5)
121 (77.1) 38 (49.4) 32 (21.8) 8 (11.1) 1.3 ± 0.7 1.3 ± 0.7
0.696 0.138 0.077 0.510 0.991 <0.0001 0.055 0.944
61 (38.9) 20 (12.7)
8 (10.3) 6 (7.7)
<0.0001 0.245
14 (8.9) 14 (8.9) 11 (7.1)
2 (2.6) 3 (3.8) 2 (2.6)
0.054 0.124 0.131
157 78 94 113
(100) (49.7) (59.9) (72.0)
77 31 41 47
(98.7) (39.7) (51.3) (60.3)
0.332 0.150 0.210 0.069
120 6 17 13
(76.4) 62 (79.5) (3.8) 3 (3.8) (11.0) 8 (10.3) (8.3) 2 (2.6)
0.599 0.626 0.868 0.074
CCS3or4, Canadian Cardiovascular class 3 or 4 angina; COPD, chronic obstructive pulmonary disease; CEA, carotid endarterectomy; TIA, transient ischemic attack; ACE, angiotensin-converting enzyme.
(range 1e20) in group I and 1.3 ± 0.9 days (range 1e7) in group II ( p ¼ NS). By the second postprocedure day, 93.6% of the younger cohort and 94.8% of patients 80 old were discharged home. Periprocedural neurological events and mortality at 30 days were similar between the groups (Table III). None of the patients in either group suffered a myocardial infarction within 30 days of CAS. There was no significant difference in the overall 30-day stroke rate between symptomatic and asymptomatic patients. The incidence of TIA was slightly higher in the octogenarian group, but
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Table II. Anatomic and procedural data
Lesion length (mm) Lesion calciuma Aortic arch type I II III Thrombus
<80 (n ¼ 157) (%)
80 (n ¼ 78) (%)
p
15.2 ± 7.0 28 (18.7)
15.2 ± 9.2 15 (20.0)
0.995 0.810
92 57 0 2
38 36 2 2
0.047
(61.7) (38.3) (0) (1.3)
(50.0) (47.4) (2.6) (2.6)
0.405
a
Percentage of patients with moderate or severe lesion calcification.
Table III. 30-day outcome <80 (n ¼ 157) 80 (n ¼ 78) (%) (%) p
TIA CVA (minor) CVA (major) CVA (fatal) Death CVA/death Access site complication Hemorrhage Acute renal failure Myocardial infarction Congestive heart failure
3 1 2 1 1 4 5 5 2 0 0
(1.9) (0.6) (1.3) (0.6) (0.6) (2.5) (3.2) (3.2) (1.3)
1 2 1 0 0 3 5 1 0 0 0
(1.3) (2.6) (1.3) (0.0) (0.0) (3.8) (6.4) (1.3) (0.0)
0.595 0.256 0.704 0.668 0.668 0.426 0.249 0.351 0.445 NS NS
TIA, transient ischemic attack; CVA, cerebral vascular accident.
the difference did not reach statistical significance. Univariate analysis demonstrated a significant relationship between absence of hypertension ( p ¼ 0.0276) and serum creatinine >1.4 ( p ¼ 0.0176) and the combined end point of stroke and all-cause mortality. On multivariate analysis, both absence of hypertension (odds ratio [OR] ¼ 0.38, p ¼ 0.0352) and chronic renal insufficiency (OR ¼ 2.62, p ¼ 0.0238) remained significant predictors of the composite end point of stroke and all-cause mortality. Mean follow-up was 17.9 ± 14.8 months (range 1e72). Kaplan-Meier analysis revealed that survival (Fig. 1) and freedom from the combined end point of stroke and all-cause mortality (Fig. 2) were similar for patients <80 and those 80.
DISCUSSION Our data suggest that carotid stenting in octogenarians is not associated with an increased risk of adverse events at 30 days or at mid-term follow-up. In elderly patients, carotid artery revascularizationdwhether by surgery or stentingdremains
controversial. Many large, single-center academic series have reported stroke and death rates of 2.2e 2.8% in octogenarians following CEA.9-11 Others have identified advanced age as an independent predictor of stroke following CEA. Goodney et al.,8 in a series of 3,092 primary CEAs performed at 11 hospitals in northern New England, found that age >70 years was associated with perioperative stroke. In some single-center surgical series, patients did not undergo independent neurological evaluation during the postoperative period, and as such, actual event rates may have been higher than were reported.21 The risk of periprocedural stroke and death following endovascular carotid revascularization also varies across studies. A number of small series, registries, and lead-in data from the CREST trial suggest that there is a marked difference in periprocedural and 30-day stroke rates in octogenarians versus younger patients.15,17,22 Stanziale and colleagues16 found an 8.0% stroke rate in octogenarians compared with a 2.7% in younger patients. Kastrup et al.17 compared CAS with CEA and found a higher rate of minor stroke, but not major stroke, in octogenarians versus younger patients. Theiss et al.23 reported a subgroup analysis of the Pro-CAS data on numerous variables that were predictors of peri-interventional stroke or death. While the rate of events in the >80 year group was higher (6.3% compared with 3.8%) than in the 70e79 year group, the difference did not reach statistical significance. The most important variable was center experience: Centers that performed more than 50 interventions per year had a lower event rate than lower-volume institutions. This study underscores the importance of experience both with the procedure and with patient selection. The authors concluded that dedicated training and strict credentialing rules for CAS were vital. Several explanationsdsymptomatic status, anatomic factors, hemodynamic instability, and operator experiencedhave been offered to account for the increased stroke rates in octogenarians following CAS. Investigators for the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausa¨rzte (ALKK) Carotid Artery Stent registry noted a difference in stroke rates in symptomatic patients of 7.1% in patients >80 compared to 3.9% in those <80 years old.22 In asymptomatic patients the difference was 3.4% vs. 2.6%, respectively. The authors suggested that the larger number of symptomatic patients in the >80 year group accounted for the increased stroke rate. In both the present series and the CREST lead-in population, no association was observed between symptomatic status and the composite variable stroke and all-cause mortality.15
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Fig. 1. Kaplan-Meier plot depicting survival following CAS. Solid line, group I (age <80); dashed line, group II.
Fig. 2. Kaplan-Meier plot showing freedom from the combined end point of stroke and death following CAS. Solid line, group I (age <80); dashed line, group II.
Certain anatomic features, such as the carotid string sign, extensive calcification, and severe vessel tortuosity, place patients, regardless of age, at greater risk for adverse outcomes. Patients >80 years old often have more complex aortic arch morphology, arch calcification, and common carotid and internal carotid artery tortuosity than younger patients,
which may lead to poorer outcomes.20,24 These features can make CAS more difficult to perform and may contribute to longer procedure times, a greater percentage of aborted procedures, and increased residual stenosis after CAS observed in octogenarians compared with their younger counterparts.22 However, these variables are not unique
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to the elderly; our data suggest that chronological age alone is an inadequate discriminator of CAS risk. Profound bradycardia as well as symptomatic hypotension or hypertension are seen more commonly in patients 75 than in younger patients. In a series by Groschel et al.,25 age 75 years predicted postprocedure hemodynamic instability (4.3% in patients <75 years vs. 10.4% in patients 75, p < 0.05) as well as the occurrence of severe medical complications such as myocardial infarction and TIAs (3.5% in patients <75 vs. 13.5% in patients 75, p < 0.05). Narrative summaries from octogenarians in the CREST leadin phase specifically noted severe tortuosity (>90 degrees) in two patients that did not allow embolic protection to be placed and hypotension and bradycardia in seven of 10 patients, all of whom suffered central nervous system events.15 Hemodynamic instability during CAS may have contributed to the higher incidence of neurological complications among octogenarians. The extent to which operator experience and patient selection influence outcomes in elderly patients is difficult to quantify. The patients in the present study were selected based on established high-risk criteria first proposed by the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial and subsequently adopted by the other high-risk trials and registries. Beyond these basic inclusion and exclusion criteria it is impossible to compare subtle operator selection bias that may have influenced patient selection for CAS. Moreover, experienced interventionalists are more likely to recognize anatomy that makes a CAS procedure treacherous and to make adjustments to minimize procedural risk than less experienced operators. Operators at all three centers included in the present study are experienced vascular interventionalists with extensive CAS experience. This may have allowed for better patient selection and exclusion of patients felt to be at inordinately high risk for stroke following CAS based on anatomic factors. The data presented herein suggest that CAS in octogenarians is not associated with an increased risk of adverse events at 30 days and at mean follow-up of 1.5 years. Our results are consistent with those Longo and colleagues,26 who found similar event rates in all age groups following CAS, with no increased risk in octogenarians. We found that renal insufficiency correlated with increased risk of the composite of any stroke and all-cause mortality. This finding is in agreement with other series that showed that renal dysfunction is associated with increased mortality following carotid
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revascularization.27-29 The relationship between absence of hypertension and the composite outcome of stroke or death remains troubling. The association was driven by all-cause mortality, not stroke, which was similar in patients with and without hypertension. We acknowledge certain study limitations. This study was a retrospective review and, compared to many other studies, represents a relatively small number of patients. Additionally, elderly patients who were not deemed appropriate for CAS were excluded and either underwent CEA or medical therapy. Patient selection was dependent on the operator, and subtle bias was not controlled for. Available data and follow-up were not designed to specifically assess factors that could have contributed to our observed outcomes compared to other studies. Factors of patient selection beyond basic high-risk criteria, specifics of procedural technique, the overall health of our older population, and racial or genetic factors may account for the difference in our observed experience. Studies designed and powered to address some of these specific issues and to further evaluate the influence of age on outcomes will be required before a definitive assessment of risk can be determined.
CONCLUSION CAS in high-risk patients can be performed safely by experienced operators. Octogenarians are not at increased risk of periprocedural adverse events following CAS compared to younger patients. Exclusion of high-risk patients from CAS based on age alone is unjustified.
The authors thank Patty Eisenbraun, RN; Robin Farley, RN; and Teresa Harwood, RN, for assistance in compiling data for this study.
APPENDIX 1 Trials represented in this study: ACT I - Asymptomatic Carotid Stenosis, Stenting Versus Endarterectomy Trial; ARCHeR ACCULINK for Revascularization of Carotids in High Risk Patients; CAPTURE - Carotid Acculink/Accunet Post Approval Trial to Uncover Rare Events (Post Market); CARESS - Carotid Revascularization with Endarterectomy or Stenting Systems; CHOICE - Carotid Stenting for High Survival-Risk Patient, Evaluating Outcomes through the Collection of Clinical
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Evidence (Post Market); CREATE-Feasability, CREATE-Pivotal, and CREATE-Spider Rx - Carotid Revascularization with ev3 Arterial Technology Evolution; EPIC US Feasability Study and EPIC US Pivotal Study - Evaluating the Use of Fibernet Embolic Protection System in Carotid Artery Stenting; MAVErIC II and MAVErIC III - Evaluation of Medtronic AVE Self Expanding Carotid Stent System with Distal Protection in the Treatment of Carotid Stenosis; PRIAMUS - Proximal Flow Blockage Cerebral Protection During Carotid Stenting; SAPPHIRE WW - Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy World Wide (Post Market); VIVA - The Bard Vivexx Carotid Revascularization Trial. REFERENCES 1. Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotidartery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004;351:1493-1501. 2. Carotid Revascularization Using Endarterectomy or Stenting Systems (CaRESS) phase I clinical trial: 1-year results. J Vasc Surg 2005;42:213-219. 3. Safian RD, Bacharach JM, Ansel GM, Criado FJ. Carotid stenting with a new system for distal embolic protection and stenting in high-risk patients: the Carotid Revascularization with ev3 Arterial Technology Evolution (CREATE) feasibility trial. Catheter Cardiovasc Interv 2004;63:1-6. 4. Gray WA, Hopkins LN, Yadav S, et al. Protected carotid stenting in high-surgical-risk patients: the ARCHeR results. J Vasc Surg 2006;44:258-268. 5. Gray WA, Yadav JS, Verta P, et al. The CAPTURE registry: results of carotid stenting with embolic protection in the post approval setting. Catheter Cardiovasc Interv 2007;69:341-348. 6. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445-453. 7. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995;273:1421-1428. 8. Goodney PP, Likosky DS, Cronenwett JL. Factors associated with stroke or death after carotid endarterectomy in northern New England. J Vasc Surg 2008;48:1139-1145. 9. O’Hara PJ, Hertzer NR, Mascha EJ, Beven EG, Krajewski LP, Sullivan TM. Carotid endarterectomy in octogenarians: early results and late outcome. J Vasc Surg 1998;27:860-870. 10. Perler BA, Dardik A, Burleyson GP, Gordon TA, Williams GM. Influence of age and hospital volume on the results of carotid endarterectomy: a statewide analysis of 9918 cases. J Vasc Surg 1998;27:25-31. 11. Mozes G, Sullivan TM, Torres-Russotto DR, et al. Carotid endarterectomy in SAPPHIRE-eligible high-risk patients: implications for selecting patients for carotid angioplasty and stenting. J Vasc Surg 2004;39:958-965. 12. Pruner G, Castellano R, Jannello AM, et al. Carotid endarterectomy in the octogenarian: outcomes of 345 procedures performed from 1995e2000. Cardiovasc Surg 2003;11: 105-112.
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13. Chastain HD, 2nd, Gomez CR, Iyer S, et al. Influence of age upon complications of carotid artery stenting. UAB Neurovascular Angioplasty Team. J Endovasc Surg 1999;6: 217-222. 14. Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomised trial. Lancet 2001;357:1729-1737. 15. Hobson RW, 2nd, Howard VJ, Roubin GS, et al. Carotid artery stenting is associated with increased complications in octogenarians: 30-day stroke and death rates in the CREST lead-in phase. J Vasc Surg 2004;40:1106-1111. 16. Stanziale SF, Marone LK, Boules TN, et al. Carotid artery stenting in octogenarians is associated with increased adverse outcomes. J Vasc Surg 2006;43:297-304. 17. Kastrup A, Schulz JB, Raygrotzki S, Groschel K, Ernemann U. Comparison of angioplasty and stenting with cerebral protection versus endarterectomy for treatment of internal carotid artery stenosis in elderly patients. J Vasc Surg 2004;40:945-951. 18. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572. 19. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-239. 20. Lin SC, Trocciola SM, Rhee J, et al. Analysis of anatomic factors and age in patients undergoing carotid angioplasty and stenting. Ann Vasc Surg 2005;19:798-804. 21. Rothwell PM, Slattery J, Warlow CP. A systematic review of the risks of stroke and death due to endarterectomy for symptomatic carotid stenosis. Stroke 1996;27: 260-265. 22. Zahn R, Ischinger T, Hochadel M, et al. Carotid artery stenting in octogenarians: results from the ALKK Carotid Artery Stent (CAS) Registry. Eur Heart J 2007;28:370-375. 23. Theiss W, Hermanek P, Mathias K, et al. Predictors of death and stroke after carotid angioplasty and stenting: a subgroup analysis of the Pro-CAS data. Stroke 2008;39: 2325-2330. 24. Bazan HA, Pradhan S, Mojibian H, Kyriakides T, Dardik A. Increased aortic arch calcification in patients older than 75 years: implications for carotid artery stenting in elderly patients. J Vasc Surg 2007;46:841-845. 25. Groschel K, Ernemann U, Riecker A, Schmidt F, Terborg C, Kastrup A. Incidence and risk factors for medical complications after carotid artery stenting. J Vasc Surg 2005;42: 1101-1107. 26. Longo GM, Kibbe MR, Eskandari MK. Carotid artery stenting in octogenarians: is it too risky? Ann Vasc Surg 2005;19:812-816. 27. Debing E, Van den Brande P. Chronic renal insufficiency and risk of early mortality in patients undergoing carotid endarterectomy. Ann Vasc Surg 2006;20:609-613. 28. Ayerdi J, Sampson LN, Deshmukh N, Farid A, Gupta SK. Carotid endarterectomy in patients with renal insufficiency: should selection criteria be different in patients with renal insufficiency? Vasc Surg 2001;35:429-435. 29. Ascher E, Marks NA, Schutzer RW, Hingorani AP. Carotid endarterectomy in patients with chronic renal insufficiency: a recent series of 184 cases. J Vasc Surg 2005;41: 24-29.