A Single Center Clinical Evaluation of Carotid Stenting for the Treatment of Obstructive Carotid Artery Disease: Experience in a

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Introduction
Carotid angioplasty and stenting (CAS) is a less invasive alternative to conventional carotid endarterectomy (CEA). CEA remains the mainstay for treatment of obstructive carotid artery disease (CAD) based on randomized trials conducted with low risk surgical patients compared with medical therapy.¹ Results of the Study of Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial have concluded that CAS with an embolic protection device is not inferior to carotid endarterectomy in high risk patients and has been shown to have fewer complications in the short term.² We report data on fifty consecutive cases utilizing a standardized carotid protocol at our institution performed by a single operator. The majority (96%) of procedures include embolic protection devices. We sought to demonstrate that carotid angioplasty and stenting can be accomplished safely and successfully in a community hospital with results comparable to those attained in clinical trials at academic centers.

Methods
Patient Population
Fifty consecutive cases were enrolled between October 20, 2001 and June 28, 2005 at Mount Clemens Regional Medical Center, Mount Clemens, Michigan. Consent was obtained at the time of enrollment. Patients were considered for CAS if one high-risk variable was present. These conditions included cervical immobility, contralateral carotid occlusion, high lesions, low or ostial lesions, prior neck radiation, prior radical neck surgery, short or obese neck, severe CAD/ angina, cardiomyopathy, severe aortic stenosis and severe chronic obstructive pulmonary disease. Symptomatic patients had a transient ischemic attack or stroke within the previous 120 days involving the ipsilateral carotid artery distribution. A symptomatic lesion had to be greater than 60% and an asymptomatic lesion had to be greater than 80% to be considered for CAS. All participants were greater than eighteen years old. Exclusion criteria included pregnancy, stroke within four weeks of the index procedure, persisting ischemic stroke (defined as either a score >/- 15 on the NIH stroke scale, a Rankin score >/- 3 or a Barthel score

The average age of the patients was 71 (54–86). Thirty-one men (65%) and 17 women (35%) were enrolled in the study. Staged bilateral carotid interventions were completed in two patients. Therefore, there were 50 vessels which underwent CAS. Risk factors for carotid atherosclerosis and co-morbid conditions of the study group are listed in Table 1. Sixteen patients (32%) were symptomatic. Indications for CAS included prior CEA 14 patients (28%), 3 patients (6%) with contralateral carotid occlusion, 4 (8%) cases, which were considered to be low or ostial lesions, and one patient (2%) had a prior radical neck surgery. CAS was undertaken in the following high risk co-morbidities — severe CAD/angina defined as > 70% stenosis of 2 or more epicardial coronary arteries or significant (> 50%) left main disease (10 cases, 20%), cardiomyopathy with New York Heart Association Class III-IV symptoms (10 cases, 20%), severe aortic stenosis (1 case, 2%) and severe chronic obstructive pulmonary disease (3 cases, 6%). Two patients did not have high-risk features but refused traditional CEA and were allowed to enroll in the study.

Baseline color duplex ultrasound imaging was obtained in a laboratory accredited by the Intersocietal Commission for the Accreditation of Vascular Laboratories (ICAVL). Carotid angiograms were obtained in all patients prior to (< 120 days) CAS. A neurological assessment was obtained by an independent, board certified neurologist prior to CAS. Baseline NIH, Barthel and Rankin stroke scales were completed. All patients were given aspirin 325 mg (unless an allergy was documented) prior to the procedure. Clopidogrel 75 mg was started 48 hours prior to the intervention and continued for four weeks post procedure or longer if indicated for cardiovascular indications. Ticlopidine (250 mg b.i.d.) was used in one patient with an allergy to clopidogrel.

Carotid Angioplasty and Stenting Protocol
All carotid interventions were performed in the cardiac catheterization laboratory. All procedures were performed by a single interventional cardiologist. Frequent neurological examinations were performed during the procedures. Intravenous sedation was minimized. Antihypertensives were held the day of the procedure.
Anticoagulation was given during the procedure. Intravenous heparin was used in 37 cases (74%). The initial bolus dose of heparin was approximately 3,000 to 5,000 units (with necessary weight adjustments). Additional bolus doses of heparin were given to maintain an ACT near 300 seconds during the procedure. Bivalirudin was given in thirteen (26%) cases. Bivalirudin was administered utilizing standard doses for coronary interventional procedures.

Due to inter-patient anatomic variability and individual lesion morphologic differences (e.g., lesion length, lesion severity, lesion eccentricity, bifurcation lesions, vessel size, vessel tortuosity, etc.), it is difficult to completely standardize operator technique for all patients and all lesion subsets. Femoral access was used in all patients with a 7 or 8 Fr sheath. Selective access to the common carotid artery was maintained with a 7 or 8 Fr long shuttle guiding catheter. Temporary pacemaker placement was done preoperatively in two cases (one case with severe aortic stenosis and one case with a significant ischemic cardiomyopathy). An embolic protection device was used in 48 (96%) cases. The first two cases in our series did not employ embolic protection devices because they were not yet available. The PercuSurge GuardWire^® (Medtronic, Minneapolis, Minnesota) system was used in our first 35 cases with neuroprotection devices. The Rx Accunet^® Embolic Protection system (Guidant Corp., Indianapolis, Indiana) was used in our last 13 cases. All lesions were predilated. Atropine (1 mg IV) was given prior to balloon inflation to prevent severe bradycardia. The self-expanding Precise^® Stent (Cordis Corp., Miami, Florida) was used in 37 cases. In the last 13 cases of our series, we used the Rx Acculink^® Carotid Stent System (Guidant Corp.). For this study, only one lesion was stented for each patient and no more than two stents were implanted to treat any one lesion. Overlapping of stents was kept to a minimum (approximately 5 mm). Different diameter stents were combined in tapering lesions. After stent deployment, postdilitation was performed to achieve optimal stent strut apposition.

All patients were admitted to the interventional telemetry unit for observation. A neurological assessment by a board certified, independent neurologist was obtained 24 hours after the procedure and prior to discharge.
Procedural results and hospital outcomes assessed included angiographic success (< 30% residual stenosis determined by angiography immediately post-stent placement), access site complications requiring surgical repair or blood transfusion, bradycardia requiring temporary pacing, myocardial infarction (MI), TIA, minor stroke (NIH ? 4, Barthel ? 90, Rankin ? 2), major stroke (NIH ? 15, Barthel ? 60, Rankin ? 2) and death. For a stroke to be minor, it must be minor on all three scales. A stroke rated as major on any scale was considered major if the deficit persisted more than three months. All patients had an electrocardiogram immediately following the procedure and the next morning. Cardiac biomarkers were drawn if the patients exhibited signs or symptoms of myocardial ischemia/ infarction.

During the follow-up period, patients had a carotid duplex ultrasound, neurologic exam and an assessment for clinical events at 1 month, 6 months and 12 months. The clinical endpoints included TIA, ipsilateral stroke, death due to a neurologic event, and restenosis, requiring another carotid intervention (CAS or CEA).
Long-term results, after the initial 12 months, were assessed retrospectively by telephone interview and chart review. All subjects were interviewed between March 24th and March 27th 2006. The clinical endpoints included TIA, ipsilateral stroke, death due to a neurologic event, and restenosis requiring another carotid intervention (CAS or CEA).

Results
Hospital Outcomes
Angiographic success (< 30% residual stenosis determined by angiography immediately post-stent placement) was obtained in all 50 carotid interventions. No transient ischemic attacks occurred. Two patients experienced a CVA after stenting (both procedures employed embolic protection devices). One patient, case # 32, had a major CVA, which resulted in death. The patient was an 85-year-old female with severe obstructive lung disease and an asymptomatic, severe de novo carotid stenosis, 80–99% by duplex ultrasound who had been turned down previously for CEA. A carotid angiogram revealed a very tortuous common carotid artery. Prior to CAS the patient and her family were told that she was high risk for the carotid intervention secondary to the tortuosity. The patient experienced a major stroke within 24 hours, and expired nine days later after continued deterioration of her condition. The other stroke, case # 22, was minor by definition. This was a 75-year-old male with a cardiomyopathy, history of congestive heart failure and multivessel coronary disease with a known asymptomatic, de novo carotid stenosis > 85%. Post procedure the patient developed symptoms consistent with a right hemispheric stroke. Pre-stenting his NIH Stroke Scale was 0, Barthel Index was 100, and Rankin Score was 0. His NIH Stroke Scale was 7, 24 hours post CAS and his Barthel Index was 55 and Rankin Score was 4.

There were no perioperative MIs. One access site complication occurred. This patient was a 65-year-old female with prior history of an aortobifemoral bypass. The patient experienced an arterial occlusion post sheath removal. The patient underwent angiography and catheter infusion of Tissue Plasminogen Activator at the site of occlusion. Distal perfusion improved with therapy and the patient was discharged 48 hours after CAS. There were no prolonged episodes of bradycardia that required tranvenous pacing. Within 24 hours of CAS, 60% of patients were discharged.

Clinical Events post CAS
One-Month Outcomes
Data were collected on 47 patients (one in-hospital expiration). There were no events at one month of follow up. The subject, who experienced a minor stroke perioperatively, had a NIH stroke scale of 4, Barthel Index of 100 and Rankin score of 1.

One-Year Outcomes
Data were collected on 47 patients. During follow up, one patient expired from non-neurologic causes (congestive heart failure). Average follow up for the study population was 11.9 months. At one year of follow up, one major ipsilateral stroke occurred in a patient with known atrial fibrillation who presented 140 days post CAS with a sub-therapeutic International Normalized Ratio (1.0). The carotid stent was patent without restenosis (by duplex ultrasound) and the stroke was thought by neurology to be cardioembolic in origin. There were no TIAs, minor strokes, or deaths among the study population. There were no cases of restenosis requiring intervention at 1 year. Duplex ultrasound detected four cases of restenosis > 50%. In two cases stenosis was > 70% by duplex ultrasound. Angiography detected restenosis of < 20% in both cases. The other two cases had 50–69% restenosis and were followed by serial ultrasound.

The subject who experienced a minor stroke perioperatively had a NIH stroke scale of 3, Barthel Index of 100 and Rankin score of 1 at both 6 months and 1 year of follow up.

Long-Term Outcomes
Long-term results were assessed by telephone interview and chart review. All subjects (or next of kin if expired) were interviewed between March 24 and March 27, 2006. Average time from procedure to telephone interview was 30.6 months (2.6 years). After one year, six more patients expired (2 from cancer, 2 from congestive heart failure, 1 from liver failure, and 1 from pneumonia). Therefore, 40 patients were interviewed by telephone. After the initial one year of clinical follow up, no subject reported a TIA, ipsilateral stroke or death due to a neurologic cause. One patient required another carotid intervention. The patient underwent CAS at another institution for reported asymptomatic, 85% in-stent restenosis. The second procedure occurred 1202 days (3.3 years) after the initial carotid intervention.

Discussion
In this small, prospective case series, the safety, feasibility and clinical outcomes of CAS were assessed. In the SAPPHIRE trial, which compared CAS with CEA in 334 high-risk patients, the conventional endpoints were stroke or death at 30 days plus ipsilateral stroke or death from neurologic causes within 31 days to 1 year. In the SAPPHIRE trial, CAS was reported to have a 5.1% incidence of these endpoints compared to an incidence of 7.5% for CEA. The difference in these endpoints was not significant. In our series, the cumulative incidence of the same endpoints was 8.0%.

Bush et al reported hospital outcomes of 51 carotid interventions in a community setting.³ Their protocol did not include use of neuroprotective devices. One major stroke and no deaths occurred in their sample and they reported a 30-day stroke and death rate of 2.0%. There is a paucity of data on outcomes of carotid angioplasty and stenting with embolic protection devices in a community setting. In a university setting, Eskandari et al reported a stroke and death rate of 2.3% at 30 days in a series that included 175 carotid interventions and neuroprotection was used in 90% of cases.⁴ The ARCHeR II trial, a registry of 278 patients, reported an incidence of major stroke and death of 2.5% at one year.⁵ All of their cases used embolic protection devices and the total stroke rate at one year was reported at 5.8%. In our series, the total stroke rate was 6.0%.

A pooled analysis of >10 industry sponsored registries (3402 patients), of which most used embolic protection devices, showed a 4% rate of periprocedural stroke and a 30 day stroke rate from 2–7%.⁶ In our series, our periprocedural stroke rate and our 30 day stroke rate were both 4%. Therefore, our results are comparable to those obtained in a large number of subjects in registry trials.

Our only periprocedural stroke and death was an 85-year-old female. Current data are inconclusive whether CAS is as safe in octogenarians as in other age groups. Kastrup et al have reported that advanced age and hemispheric TIA are clinical predictors of transient ischemic attack, stroke or death within 30 days of CAS.⁷ Longo et al reported that CAS in octogenarians is comparable to other age groups.⁸ However, this study included only 29 patients > 80 years old. Another case series, compared adverse outcomes between 87 octogenarians and 295 nonoctogenarians and found that at one year of follow up, only 75% of octogenarians as opposed to 87% of nonoctogenarians were free from stroke, MI, or death.⁹ In this report, 30 day stroke rate was 8.0% for octogenarians as opposed to 2.7% of nonoctogenarians. In this study, embolic protection devices were used in 62% of octogenarians and 52% on nonoctogenarians. Randomized data in this patient population are necessary.

There was a low incidence of non-neurologic events among our series. There were no periprocedural MIs in our study group. This finding may be explained by the fact that most of the patients had known coronary artery disease and may have been receiving appropriate secondary preventive measures. Of the patients enrolled in our case series, 87.5% had known CAD. There was a very low incidence (2%) of access site complications. The one case which had a complication had known severe peripheral vascular disease with prior aortobifemoral bypass surgery. In our series, no cases required temporary pacing after the procedure. Prophylactic atropine administration before balloon inflation, during CAS may have reduced the incidence of severe bradycardia in our interventions.¹⁰ Although not an endpoint in our trial, post-procedural hypotension was recorded in 6 (12%) patients. Hypotension was asymptomatic, required dopamine in the minority of cases, and all events lasted less than 24 hours. Another series reported an incidence of 5% for post procedural hypotension.¹¹ Risk factors have been reported previously and include coronary artery disease and elderly patients.¹² All of our patients which had hypotensive episodes had CAD and four patients had cardiomyopathies.

In our series, we had no cases that required a second intervention at one year. Duplex ultrasound follow up detected four cases of restenosis > 50%. In two cases, stenosis was estimated a > 70%, but upon angiography the detected restenosis was < 20% in both cases. It was felt that the discrepancy of lesion severity between the two imaging modalities may have been secondary to accelerated velocities post stent placement on the duplex ultrasound.

Our long-term data suggest that carotid angioplasty and stenting is a durable procedure. In our series, with an average follow up of 2.6 years, one case required CAS for restenosis. This procedure occurred 3.3 years after the initial intervention. The ELOCAS registry, a database of 4 high volume European centers, recently published their restenosis rates in 2172 patients.¹³ Restenosis rates of 1%, 2%, and 3.4% at 1 year, 3 years and 5 years, respectively, were reported. Restenosis was examined in a single center report of 221 carotid interventions and found restenosis rates at 6 months, 1, 2 and 4.5 years were respectively 1.4%, 2.3%, 3.7%, and 5.9%.¹⁴ Our rate of re-intervention was 2%. The total ipsilateral stoke rate at 2.6 years average follow up was 6%.

Limitations and Recommendations
This was a small, non-randomized, prospective case series. The generalizability of the study findings is somewhat limited due to the number of patients enrolled.

Although carotid angioplasty and stenting is feasible and appears to be safe and effective in a community setting in high-risk patients, further studies should focus on who should be performing CAS, how these physicians are trained, institutional requirements and whether this procedure could benefit a lower risk population.

Conclusions
In comparison to outcomes from large academic centers and multi-center trials, our data suggest that carotid angioplasty and stenting with the use of an embolic protection device is safe and effective in high-risk patients when performed in a community hospital.