ABSTRACT: Background. Fear of distal embolization and stroke has aroused concern regarding carotid stenting. Devices to protect the cerebral circulation may make carotid stenting safer. Methods. A multidisciplinary study group tested a balloon occlusion/aspiration emboli entrapment device in conjunction with carotid stenting. The device consists of an elastomeric balloon on a steerable wire with a detachable adapter that inflates and deflates the distal temporary occlusion balloon. An aspiration catheter is used to remove trapped emboli after stenting and before occlusion balloon deflation. Results. Seventy-five patients with severe internal carotid artery stenosis were treated using stents deployed with this cerebrovasculature protection system. All 75 patients (100%) had grossly visible particulate material aspirated, and all were treated successfully without major or minor stroke or death at 30 days. Pre-intervention stenosis was 81 ± 10% and residual was 5 ± 7%. Nine patients (12%) had angiographic evidence of thrombus before intervention, but no patient had thrombus or vessel cut-off after the procedure. Four patients (5%) developed transient neurologic symptoms during protection balloon occlusion, but symptoms resolved with balloon deflation. Twenty-two to 667 particles aspirated per patient ranged from 3.6 to 5,262 µm in maximum diameter, with a mean of 203 ± 256 µm. These particles included fibrous plaque debris, lipid/cholesterol vacuoles and calcific plaque fragments. Conclusions. Protected carotid stenting can be performed safely. Emboli are universal with stenting, and cerebral protection will likely be necessary to minimize stroke. Randomized trials comparing protected carotid stenting to endarterectomy are warranted. Carotid artery atherosclerosis is a major cause of disabling stroke and death. Compared to medical therapy, surgical endarterectomy has been proven to decrease stroke in both symptomatic1–3 and asymptomatic4 patients with severe stenosis. However, carotid plaque is friable, and stroke can occur despite meticulous technique and placement of intraoperative shunts.5,6 In addition, patients with carotid disease are frequently elderly with significant co-morbid disease. Even in experienced centers, carotid endarterectomy has an acceptable but significant risk of peri-operative arrhythmia, congestive failure, myocardial infarction and death. Because of the success of percutaneous stenting of atherosclerotic lesions in other arterial systems,7–10 several centers have investigated the less invasive alternative of stenting severe carotid stenoses.11–16 However, fear of distal embolization of plaque fragments to the brain has generated concern regarding the safety and wisdom of this approach, especially considering the established low risk and durability of endarterectomy.17,18 The incidence of stroke generally reported with carotid stenting is 5–10%,11–16 though one center reported stroke in 71% of an early series.19 Transcranial Doppler studies suggest the universal occurrence of emboli associated with this procedure.20 Therefore, most clinicians have avoided carotid stenting except in patients with high surgical risk or surgically inaccessible lesions. Systems to guard against distal embolization during percutaneous intervention have recently been developed. The Percusurge GuardWire™ (Percusurge Inc., Sunnyvale, California) emboli entrapment and aspiration system was tested in vitro, utilized in animals, and subsequently in human saphenous vein graft interventions.21–23 The first protected carotid artery intervention cases with this system began in 1998.24 A multidisciplinary group of physicians (a surgeon, an interventional neuroradiologist, 3 interventional radiologists, and 3 interventional cardiologists) treating patients with carotid disease agreed to evaluate this emboli containment and aspiration system in patients undergoing carotid artery stenting. These are the results of this investigation. Methods Study population. Patients with symptomatic carotid artery lesions >= 60% by angiography, or asymptomatic patients with lesions >= 70% were considered for this study. Patients with a stroke within 1 week and patients with 100% occlusion of the ipsilateral carotid artery were excluded. The study protocol was approved by the Institutional Review Board at each institution, and the patient signed informed consent to undergo this investigational procedure. Carotid stenting procedure. Patients were treated with aspirin 81–325 mg/day for at least 24 hours and underwent an independent neurologic examination at baseline. The patient was taken to the angiographic laboratory with an intravenous line infusing. A 7–9 French sheath or guiding catheter was placed in the common carotid artery according to standard techniques11–16 after local anesthesia. The patient was anticoagulated with 50–100 units/kg heparin until the activated clotting time (ACT) was > 250 seconds. Angiograms were recorded in at least two projections. Intracranial views were also documented. The cerebral protection system utilized consists of 3 components: an exchange length guidewire, a MicroSeal™ adapter, and a monorail aspiration catheter. The wire is a 0.014´´ or 0.018´´ angioplasty style wire with a segment of hollow nitinol hypotube. The distal wire segment is shapeable, radiopaque and steerable. Just proximal to this platinum distal segment is a compliant latex balloon capable of occluding blood flow when inflated to 5.5–6.0 mm. The proximal end of the hypotube wire incorporates a moveable seal allowing inflation and deflation of the balloon via the detachable adapter. After shaping the distal tip, the guidewire is advanced through the guide catheter under fluoroscopic guidance. The wire is steered through the carotid stenosis and advanced at least 3 cm beyond the target lesion (Figure 1). The intended pre-dilatation balloon, stent and post-dilatation balloon are all prepped and available. The first device to be utilized in the lesion (pre-dilatation balloon or stent, at operator discretion), is passed over the wire into the distal guiding catheter. The MicroSeal™ adapter is then attached and the latex balloon is inflated to 5.5 mm diameter. Contrast is injected to confirm complete occlusion of distal flow. If flow is still present, then an additional 0.5 cc of diluted contrast is added to enlarge the balloon until complete occlusion is achieved. The MicroSeal™ is then closed and the adapter removed. The pre-dilatation balloon (if utilized) is passed across the lesion and inflated until any indentation of the balloon is resolved. The dilatation balloon is then deflated and removed. The stent is then placed over the guidewire and deployed in the lesion. The stent delivery system is removed, and the post-dilatation balloon is then passed over the guidewire into the lesion. A single balloon inflation of 8–15 atmospheres for 15–20 seconds is performed. The balloon is deflated and then removed. The aspiration catheter is placed under fluoroscopy up to the level of the distal occlusion balloon. Fifteen to 45 ml of blood are then aspirated from the area between the carotid artery bifurcation and the occlusion balloon. The aspiration catheter is removed. The occlusion balloon is then deflated restoring antegrade flow. Most procedures were completed with only one occlusion balloon inflation, aspiration and deflation. In the first 3 cases and in 4 additional cases of the series, the aspiration was performed and the occlusion balloon deflated after 1–2 steps of a sequential procedure, i.e., after pre-dilatation followed by aspiration and occlusion balloon deflation, after stent placement followed by aspiration and occlusion balloon deflation, and after stent post-dilatation followed by aspiration and occlusion balloon deflation. By the sequential approach, each step occlusion time could be minimized at operator discretion. After final occlusion balloon deflation and removal, angiography was repeated confirming adequate lumen diameter in at least 2 orthogonal views. Intracranial views were repeated to check for vessel cut-off or flow abnormality. The patient underwent frequent brief neurologic assessments during the procedure (question and answers, hand and foot movement) and a detailed neurologic evaluation at the end of the procedure. The patient was taken to a recovery area where the sheath was removed when the ACT was Particulate analysis. Aspirated blood was injected from a syringe into a container through a 40 µm filter. The filter was rinsed by injection of 20–60 cc saline, and then immersed in either 10% buffered formaldehyde or 2.5% glutaraldehyde in cacodylate buffer. Particulate debris from 31 consecutive patients was sent to a core pathology laboratory (JM) for analysis. After 24 hour fixation, the mesh of the filters was carefully cut from its frame and mounted on glass slides, stained with toluidine blue 1% and covered with a cover slide. Digitized black and white images were used for measurement. The Optimas Analysis Program, version 5.0, was employed. Each of 4,215 particles were manually selected and the major diameter of the particles was measured. In 2,000 particles, area was also measured. In 7 patients, particles floating in the fixative were centrifuged, and a smear was stained with hematoxylin/eosin. Data analysis. The primary endpoint of the study was the composite of death or non-fatal stroke at 30 days. Secondary endpoints were balloon occlusion intolerance, transient ischemic attack, arrhythmia, congestive heart failure, myocardial infarction, pulmonary complications extending hospitalization, and access site complications. The study was designed as a prospective registry to determine the feasibility and complications of protected carotid stenting. Data are reported as mean ± 1 SD. The investigators agreed to compile the data and analyze the results after the first 50–75 cases had been completed. An independent group of monitors audited and source verified the data at each institution before analysis. Results The first 75 consecutive eligible patients were enrolled at the participating centers. Baseline patient characteristics are included in Table 1. Fifty-six percent of patients had previous transient hemispheric or ophthalmic symptoms. Twenty-three patients (31%) had significant contralateral or intracranial carotid artery disease. Lesion characteristics are listed in Table 2. Nine lesions had angiographic evidence of thrombus, and lesion length was > 20 mm in 27 patients (36%). Procedural details are compiled in Table 3. Four patients (5%) had balloon occlusion intolerance with transient neurologic symptoms which resolved after balloon deflation. One patient had adjunctive thrombus aspiration with the Possis AngioJet™ (Possis Inc, San Diego, California). No angiographic evidence of vessel cut-off or flow abnormality was seen. Neurologic examinations (immediate post-procedure and next day) confirmed no evidence of stroke after the procedure. One patient with sustained hypotension (systolic blood pressure 70%, had a transient ischemic attack resolved with restoration of systolic blood pressure > 100 mmHg. No unstable angina, ventricular arrhythmia or myocardial infarction occurred. One patient developed pulmonary edema after being given a rapid infusion of saline for relative hypotension (systolic blood pressure 90–100 mmHg) immediately after stenting. This patient responded to diuresis and medical management. Three patients required transfusion for bleeding. Two of these patients required surgical femoral artery repair. At 30 days, repeat neurologic examination revealed no incidence of cerebrovascular accident, and no patient reported symptoms consistent with transient ischemic attack after hospital discharge. No patients died or were rehospitalized at 30 days. Particulate debris was visible in all aspiration samples (Figure 2). The number of particles analyzed per patient ranged from 22–667. The mean maximum diameter was 203 ± 256 µm. Particles ranged from 3.6–5,262 µm maximum diameter. Forty-one percent of particles were 2 in area. The mean area of the particles was 279.4 µm2. On microscopic examination, these particles consisted of lipid vacuoles with cholesterol clefts surrounded by fibrin and platelets, fibrous eosinophilic staining material consistent with connective tissue from the cap of a plaque, calcific plaque fragments, lymphocyte clusters and platelet clumps (Figure 3). Discussion Fear of embolizing plaque fragments distally into the brain during carotid stenting has dampened enthusiasm for this technique, especially considering the established safety and efficacy of carotid endarterectomy. One small randomized study of carotid stenting versus surgery19 was prematurely terminated because of an unacceptable incidence of stroke with stenting (71%), though several clinical reports are more encouraging.11–16 In a non-monitored, voluntary registry of 2,048 carotid stenting cases, the incidence of death and stroke was reported to be 5.8%.15 Despite the absence of neurologic deficits in most patients, transcranial Doppler monitoring suggests that emboli are a frequent sequelae of wire manipulation, balloon dilatation and stenting. The debris aspirated in every patient in this study supports this contention. The large maximum diameter of many particles (200–1,000 µm in 35%) and the number of retrieved emboli are a cause for concern. Several devices to trap emboli have been conceived and developed. Theron reported his experience with the first cerebral protection device, but that device has not been universally adopted for carotid stenting because of its limited steerability and relatively large profile. This first generation device also did not eliminate emboli or clinical complications.24–26 Since Theron’s pioneering efforts, emboli containment devices have evolved. The system tested in this study was examined and scrutinized by the investigators, and felt to be encouraging enough to warrant a clinical trial with carotid stenting. The data collected are strikingly positive. The 100% success rate and the elimination of stroke in 75 consecutive cases of protected carotid stenting are judged by the investigators to be a major clinical advance. The presence of visible particles aspirated from all patients and the absence of stroke as a complication support the use of an emboli containment system in cases of percutaneous carotid intervention. The ease of use of the balloon on a wire and its adaptability into the clinical practices of interventionists in vascular surgery, radiology, neuroradiology and cardiology were established in this study. Pathological analysis of the aspirated material suggests that emboli are an expected consequence of carotid stenting. The data imply that some protection device will be necessary to limit carotid stenting complications, possibly to the level expected with the established gold standard of carotid endarterectomy. Clearly there will be further improvements in carotid stenting equipment and in cerebrovascular protection devices over the next few years. However, the device studied in this trial has evolved sufficiently to warrant routine use as an adjunct to carotid stenting. The emboli containment device tested does have the limitation of not stopping distal embolization until the occlusion balloon is inflated. Crossing the lesion with this balloon on a wire does create transcranial Doppler signals suggesting microemboli, but the number of emboli counts is only a fraction of those found with unprotected stenting.27 In addition, this device does transiently interrupt antegrade flow in the carotid artery. However, most patients (95% in this series) tolerate temporary balloon occlusion without symptoms, and all patients could be treated successfully with serial inflation/deflation cycles in those patients manifesting transient symptoms. The emboli entrapment/aspiration system tested appears to provide adequate protection to the cerebral circulation to make carotid stenting a viable alternative to endarterectomy in patients with high surgical risk, and perhaps even in patients who are routine surgical candidates. Trials of carotid stenting without cerebral protection may be hazardous for patients, and have little long-term clinical impact. However trials of protected carotid stenting versus carotid surgery should be expedited.
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