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Contralateral carotid artery occlusions (CCO) are associated with adverse neurologic events following carotid endarterectomy (CEA). The characteristics and outcomes of patients with CCO undergoing elective carotid artery stenting (CAS) have not been completely studied.
In-hospital outcomes were examined in patients with and without CCO undergoing elective CAS in the Carotid Artery Revascularization and Endarterectomy (CARE Registry®). A CCO was defined as a 100% occlusion of the contralateral internal carotid artery. The primary endpoint was a composite of in-hospital death, nonfatal myocardial infarction, and nonfatal stroke.
Between 2005 and 2010, 8,416 patients underwent elective CAS, of whom 900 (12%) had CCO. Patients with CCO were younger (69 vs. 71 years, p<0.001), more often male (68% vs. 61%, p<0.001), more frequently had symptoms due to the target lesion (46% vs. 39%, p<0.001), had a prior neurologic event (56% vs. 45%, p<0.001), and more frequently had restenosis in a target lesion after previous CAS (5% vs. 3%, p<0.001). The primary composite endpoint occurred in 14 (1.6%) and 211 (2.8%) patients with and without CCO, respectively (adjusted OR 0.58, 95% CI 0.33-1.00, p=0.052).
In the CARE registry, there was no evidence that the presence of a CCO was associated with an increased risk of in-hospital death, non-fatal myocardial infarction or stroke in patients undergoing elective carotid artery stenting. These findings may have implications on the selection of carotid revascularization procedures for such patients.
Stroke is the third leading cause of death after coronary artery disease and cancer, with 795,000 annual new or recurrent events in the United States1. More than 80% of all strokes are ischemic in origin2. While carotid endarterectomy (CEA) is superior to medical therapy for stroke prevention in asymptomatic and symptomatic patients with carotid artery stenosis3, patients with high risk contralateral carotid occlusions (CCO) which occur in 6-10% of patients undergoing CEA, are at much greater risk of periprocedural death, nonfatal myocardial infarction, or stroke3. Evidence to date from high-risk CEA patients suggests that elective carotid artery stenting (CAS) performed by an experienced operator is preferred in carefully selected patients4. However, data quantifying the prevalence and outcomes of elective CAS in patients with a CCO have not been completely described. In this study, we compared in-hospital outcomes between patients with and without CCOs undergoing elective CAS in the nationwide Carotid Artery Revascularization and Endarterectomy (CARE) registry.
The CARE Registry® was launched in 2007 by the NCDR® (National Cardiovascular Data Registry) as a nationwide program for carotid revascularization procedures to measure patient outcomes and ensure quality improvement. A description of CARE has been previously published5. Briefly, 186 centers in the United States voluntarily participate in collection and validation of demographic, medical history, and procedural data from patients undergoing either CAS or CEA. Data are collected from existing medical records using standardized definitions, collection protocols, and tools. An on-site registry manager is designated by each participating center to ensure data accuracy and timely submission to NCDR.
For the purpose of this study, we identified patients with and without a CCO undergoing elective CAS between 05/2005 and 03/2010. Patients were stratified by presence or absence of neurologic symptoms related to the target lesion within the past 6 months and by age <70 or ≥ 70. Patients with an acute evolving stroke (AES) including acute cerebrovascular accident in evolution or transient ischemic attack (N=204), or spontaneous carotid artery dissection (N =93) were excluded. AES required the patient to have ongoing ischemia with symptoms at the time of the procedure. AES also required each of the following: Sudden development of neurologic deficits attributable to cerebral ischemia or infarction, onset of symptoms occurring within the prior 3 days of CAS and progressively worsening symptomatology.
CCO was defined as a 100% occluded contralateral internal carotid artery. The CCO indicator was missing in one patient.
The primary clinical endpoint was a composite of in-hospital death, nonfatal myocardial infarction or nonfatal stroke. Secondary endpoints were the individual components of the composite.
Post CAS ischemic stroke was defined as a focal neurologic deficit in the absence of documented intracranial hemorrhage with residual symptoms lasting ≥24 hours and combined with impaired functional outcomes. Symptoms of ischemic stroke were identified as 1) right hemispheric or retinal, 2) left hemispheric or retinal, 3) vertebrobasilar, or 4) unknown.
Post CAS myocardial infarction was identified by an increase and decrease in cardiac biomarkers (preferably troponin) with >1 value above the upper limit of normal along with clinical evidence of myocardial ischemia consisting of ≥1 of the following: 1) symptoms, 2) electrocardiographic (ECG) changes (new ST-T changes or left bundle branch block), 3) development of pathological Q waves in the ECG, or 4) new loss of viable myocardium or new regional wall motion abnormality as evidenced by imaging6. Cardiac biomarkers were collected at the discretion of each participating investigator following CAS.
Neurologic symptoms status in the target lesion was determined in all patients prior to CAS. Symptomatic patients had history of prior carotid transient ischemic attack with distinct focal logical dysfunction persisting less than 24 hours, nondisabling stroke with a modified Rankin scale less than 3 and symptoms greater than 24 hours or transient monocular blindness (amaurosis fugax) within the previous six months.
An acute cerebrovascular accident was classified as sudden development of a neurological deficit attributable to cerebral ischemia or infarction, symptom onset within 3 days prior to and ongoing at the time of procedure, or progressively worsening numbness or weakness, difficulty speaking or understanding, blurred or impaired vision, dizziness, or loss of balance and coordination.
Data are presented as means with corresponding 95% confidence intervals (CI), counts with percentages, or medians with interquartile ranges. Baseline characteristics of patients with and without CCO undergoing elective CAS were compared using chi-square tests for discrete variables and Student’s unpaired t-tests for continuous variables. To address potential confounder in the primary endpoint, a saturated multivariable logistic regression model was developed to predict the primary outcome while adjusting for: age, gender, renal function, smoking, hypertension, hyperlipidemia, peripheral arterial disease, diabetes, chronic obstructive pulmonary disease, major surgery planned within the next 8 weeks, previous neck radiation or neck surgery (other than CEA), ischemic heart disease, myocardial infarction within the past 6 weeks, Canadian Cardiovascular Society (CCS) or New York Heart Association (NYHA) functional class III or IV heart failure within the past 6 weeks, history of atrial fibrillation or flutter, moderate to severe aortic stenosis, previous carotid artery intervention, neurological events prior to the CAS procedure, target lesion symptoms within the past 6 months, and restenosis in the target vessel after prior CAS or CEA.
Results are reported as unadjusted and adjusted odds ratios (OR) with 95% CI for the primary and secondary endpoints. For individual endpoints with no events, exact logistic regression was used to obtain ORs (95% CI). The primary endpoint was also stratified by asymptomatic and symptomatic patients and by age less than or greater than or equal to 70 years. All statistical analyses were performed using the SAS version 9.2 (SAS Institute, Cary, North Carolina). A two-sided p-value ≤ 0.05 was considered statistically significant.
Between 05/2005 and 03/2010, 8,416 patients underwent elective CAS at 151 participating CARE centers. The median (IQR) number of CAS procedures by center was 33 (13-68). Of these patients, 900 (12%) had a CCO prior to the index procedure (IQR= 5-18.6% across centers).
Baseline, neurologic, and procedural characteristics for patients with and without a CCO are presented in Table 1. Patients with CCO were younger, more frequently male, more likely past or current smokers, have a history of recent myocardial infarction, and experience neurological events prior to CAS. Non-CCO patients were more likely to have undergone previous CAS, while CCO patients were more likely to have had a previous ischemic stroke, restenosis, or symptoms of a target lesion (Table 1).
In-hospital events for the total cohort as well as by age and symptom subgroups are shown in Table 2. The primary composite endpoint occurred in fewer CCO than non-CCO patients. The difference was not statistically significant after multivariable adjustment (OR 0.58, 95% CI 0.33-1.00, p=0.052). There were numerically fewer individual myocardial infarction or stroke events in the CCO group, but the differences with non-CCO patients were not statistically significant (Table 2). When stratified by symptom status or age, the presence or absence of a CCO was not associated with a difference in the primary endpoint between asymptomatic (p=0.057) or symptomatic (p=0.41) patients or among patients younger (p=0.61) or older (p=0.053) than 70 years (Table 2).
In this nationwide registry of patients undergoing carotid artery revascularization, the prevalence of contralateral carotid occlusions in patients undergoing elective coronary artery stenting was 12%. The rate of composite in-hospital events, including death, nonfatal myocardial infarction, and nonfatal stroke did not differ between patients with and without a CCO after elective CAS. Lastly, CCO was not associated with higher complications following CAS in the elderly or individuals with prior neurologic symptoms.
The prognosis of medically treated patients with carotid artery stenosis and a CCO is poor, with two-year stroke rates ranging from 40-70%7,8. This excess risk is believed to be related to inadequate collateral circulation at the level of the circle of Willis9 from compromised ipsilateral blood supply in the setting of a complete CCO. CCO is also considered a high-risk anatomical criterion for CEA according to a recent consensus statement3. Both asymptomatic10 and symptomatic7 patients with carotid artery stenosis who undergo CEA in the context of a CCO are at higher risk for perioperative stroke compared to those without a CCO. While the mechanism for increased risk is not fully understood it is commonly believed to be related to a reduction in blood flow during cross clamping of the ipsilateral common carotid artery during endarterectomy11.
To the best of our knowledge, the clinical efficacy and safety of CAS in patients with carotid stenosis and a CCO has been evaluated in only six previously published, retrospective studies16-21, with a combined sample size of 485 patients who underwent CAS in the setting of a CCO. As expected, these studies varied widely in terms of design, and sample size ranging from 1812 to 19113. Other limitations were single center design12,14-16, only three used distal protection devices on a routine basis12,13, and only two had a control group of patients without a CCO13,17. Nevertheless, event rates in these studies ranged from 0 to 7.7% for death and 0 to 2.1% for major CVA, both in agreement with results from the present analysis. Finally, in-hospital event rates for mortality and major CVA in a recent multicenter registry were 1.6 vs. 1.4% for patients with and without a CCO undergoing CAS. Our work also represents the largest sample size to date assessing outcomes of CCO patients undergoing CAS with the widespread application of distal embolic protection devices, therefore reflecting contemporary CAS practice in the United States.
Although we did not directly compare the outcomes of CEA with CAS in patients with a CCO in the CARE registry, CEA is known to be associated with increased risk in the presence of CCO, whereas CAS appears to be safe in this group of patients potentially due to the widespread implementation of embolic protection devices during balloon inflation and stent deployment. Further, CAS appears to play an important role in the management of CCO patients, if anatomically suitable for CAS.
Several important limitations associated with our study should be noted. First, intermediate and long term follow up for CARE patients is not available. As a retrospective observational analysis, by implication, a degree of unmeasured confounder is inherent. Finally, we did not compare outcomes of CAS in the setting of a CCO with either medical therapy or CEA. According to recent results from the CARE registry18, the characteristics of patients referred for CAS differ markedly from those referred for CEA, with more comorbidities in patients referred for CAS, thus making comparisons of the two treatment strategies from observational databases problematic. Nonetheless, we believe that an indirect inference regarding the potential advantages of CAS relative to other strategies in this group of patients is warranted.
In this study, approximately 12% of CAS procedures were performed in a setting of a CCO. There was no evidence that the presence of a CCO was associated with an increased risk of in-hospital death, non-fatal myocardial infarction or stroke in patients undergoing elective carotid artery stenting. These findings may have implications on the selection of carotid revascularization procedures for such patients.
CARE Registry® is an initiative of the American College of Cardiology Foundation, the Society for Cardiovascular Angiography and Interventions, the Society of Interventional Radiology, the American Academy of Neurology, the American Association of Neurological Surgeons/Congress of Neurological Surgeons, the Society for Vascular Medicine and the Society of Vascular and Interventional Neurology.
The authors would like to acknowledge Joseph Murphy and Sandra Brennan for publication coordination and editorial assistance.
Dr. Marso reports no personal conflicts of interest during the previous 12 months. All compensation for his research activities, including research grants and consulting fees from The Medicines Company, Novo Nordisk, Abbott Vascular, Amylin Pharmaceuticals, Boston Scientific, Volcano Corporation, and Terumo Medical, are paid directly to the Saint Luke’s Hospital Foundation of Kansas City.
Conflict of interest disclosure: Dr. Cohen receives consulting income from Medtronic and Abbott Vascular and research grant support from Medtronic, Abbott Vascular, Boston Scientific and St. Jude Medical. Dr. Spertus has a contract with the American College of Cardiology Foundation for the analysis of the CARE registry.