Safety and efficacy of local periadventitial delivery of sirolimus for improving hemodialysis graft patency: first human experience with a sirolimus-eluting collagen membrane (Coll-R).

BACKGROUND: Neointimal hyperplasia causes a high rate of hemodialysis synthetic graft failure. Thus, therapies that inhibit neointimal hyperplasia are urgently needed. The Coll-R is a sirolimus-eluting collagen matrix designed for intra-operative perivascular implantation around the graft-venous anastomosis. Sirolimus is an anti-proliferative drug that has proven clinical utility in suppressing neointimal tissue growth in coronary artery disease when delivered locally to the vascular wall by an endovascular drug eluting stent. METHODS: A cohort of 12 chronic hemodialysis patients underwent surgical placement of 13 polytetrafluoroethylene grafts + Coll-R and were followed for up to 24 months. The primary endpoint was safety (freedom from device related adverse events). Secondary endpoints were pharmacokinetics of sirolimus release, success of Coll-R implantation and primary unassisted graft patency. RESULTS: There were no technical failures, infections, vascular anastomotic or wound-healing problems. Whole blood sirolimus levels rose to a mean peak of 4.8 ng/mL at 6 h and fell to <1 ng/mL at 1 week (n = 5). Twelve and 24-month primary unassisted patencies were 76 and 38%, respectively, and the thrombosis rate was 0.37/patient-year. CONCLUSIONS: Perivascular implantation of the Coll-R during graft surgery safely delivered sirolimus to the vascular wall. Systemic sirolimus levels were sub-therapeutic for immunosuppression. This small first-in-human study supports the concept that the Coll-R can safely deliver sirolimus to the graft-venous anastomosis. Safety and patency in this small study were sufficiently encouraging to justify randomized controlled trials to further test the efficacy of the Coll-R.

One-year clinical outcomes, midterm survival, and predictors of mortality after carotid stenting in elderly patients.

BACKGROUND: It has been demonstrated recently that carotid stenting can be performed safely in patients > or =80 years of age. However, it is uncertain whether these patients will derive benefit because longevity after revascularization is an important consideration. This study was conducted to determine survival and predictors of mortality of selected elderly patients after stenting. METHODS AND RESULTS: One hundred forty-two consecutive elderly patients who were non-high risk for stenting underwent 153 procedures. Patients had either symptomatic stenosis > or =50% or asymptomatic stenosis > or =70%. Demographics and in-hospital outcomes were entered into a database; subsequent outcomes and mortality data were obtained retrospectively. Mean+/-SD age was 83.3+/-3.1 years. Symptomatic patients accounted for 28%. Overall survival at 3 years was 76% (85% at 2 years). At 1 year, 1 fatal stroke had occurred, with 97% of survivors (n=114) free of neurological events (neurological status was undetermined in the remaining 3%). Predictors of mortality were remote (> or =6 months) transient ischemic attack or cerebrovascular accident, smoking history, and creatinine clearance (hemoglobin level showed a strong trend toward achieving significance); for the asymptomatic subgroup, predictors of mortality were smoking history, previous carotid endarterectomy, hemoglobin level, and increasing age. In particular, symptom status and sex were not independent predictors of mortality. CONCLUSIONS: This study demonstrates that in selected elderly patients, a high proportion (85%) survived 2 years and >75% survived 3 years after stenting. Carotid stenting may be considered a revascularization option in such patients. Better selection of patients using the predictors of mortality may help to reduce unwarranted procedures and to optimize survival likelihood.

Carotid artery stenting in elderly patients: importance of case selection.

OBJECTIVES: This study was conducted to determine if carotid stenting (CS) could be safely performed in the elderly. BACKGROUND: Age has been shown to be a predictor of neurological complications during CS. We postulated that CS could be safely performed in elderly patients if certain anatomical and clinical markers such as excessive vascular tortuosity, heavy concentric calcification of the lesion, and decreased cerebral reserve were avoided. METHODS: From July 2003 to October 2007, 142 patients aged > or =50% or asymptomatic stenosis > or =70%. All patients underwent carotid and cerebral angiography to determine anatomic suitability and stent risk. Demographic and outcome data were entered into a database; other data were obtained retrospectively. Independent neurology evaluation was performed before and at 24 hr after the procedure. RESULTS: The mean age was 83.2 years, 62% were male, 25.5% were symptomatic, 8.5% had postcarotid endarterectomy restenosis, and 6.0% had contralateral internal carotid artery occlusion. There were no intracranial hemorrhages or periprocedural myocardial infarctions. One patient had amaurosis fugax. There were two minor and three major strokes in-hospital (3.3%). All patients had 30-day follow-up. One of the major strokes expired. Thus the overall 30-day stroke or death rate was 3.3% and major stroke or death rate was 2.0%. The 30-day stroke or death rate was 5.1% for symptomatic patients and 2.6% for asymptomatic patients. CONCLUSION: CS can be performed safely in anatomically suitable elderly patients with low adverse event rates. CS should remain a revascularization option in appropriately selected elderly patients.

Multicenter evaluation of carotid artery stenting with a filter protection system.

OBJECTIVES: The aim of this study was to evaluate the feasibility and safety of carotid artery stenting (CAS) with a filter protection system. BACKGROUND: Neurologic events linked to the embolization of particulate matter to the cerebral circulation may complicate CAS. Strategies designed to capture embolic particles during carotid intervention are being evaluated for their efficacy in reducing the risk of these events. METHODS: Between September 1999 and July 2001, a total of 162 patients (164 hemispheres) underwent CAS with filter protection (NeuroShield, MedNova Ltd., Galway, Ireland) according to prospective protocols evaluating the filter system at three institutions. RESULTS: Angiographic success was achieved in 162 of the procedures (99%) and filter placement was successful in 154 (94%) procedures. Carotid access was unsuccessful in two cases (1%) and filter placement in eight cases (5%). Of the latter, five procedures were completed with no protection and three were completed using alternative protection devices. On an intention-to-treat basis, the overall combined 30-day rate of all-stroke and death was 2% (four events: two minor strokes and two deaths). This includes one minor stroke in a patient with failed filter placement and CAS completed without protection. There was one cardiac arrhythmic death and one death from hyperperfusion-related intracerebral hemorrhage. There were no major embolic strokes. CONCLUSIONS: Carotid artery stenting with filter protection is technically feasible and safe. Early clinical outcomes appear to be favorable and need to be confirmed in a larger comparative study.

Carotid artery stent placement with distal balloon protection: technical considerations.

BACKGROUND AND PURPOSE: Most neurologic events that complicate the carotid artery stent placement procedure are embolic. Strategies are being developed and evaluated for their ability to minimize the clinical embolic risk. The purpose of this study was to determine the feasibility, safety, and technical considerations of performing carotid artery stent placement with use of a distal balloon antiembolization system. METHODS: Carotid artery stent placement with use of a commercially available distal balloon antiembolization system was performed in 303 patients (325 vessels). Clinical neurologic complications were adjudicated at the time of intervention and at 1 month. RESULTS: Technical success was achieved in all but one case, with reduction of the mean percentage carotid artery stenosis from 79 +/- 9% to 3 +/- 8%. Intolerance to internal carotid artery occlusion occurred in 11 patients (3.6%); in one patient the procedure was aborted, and in 10 the procedures were expeditiously completed with no adverse neurologic events. The 30-day combined rate of all occurrences of stroke and death was 2%. These events included three (0.9%) retinal emboli, three (0.9%) minor strokes, and one (0.3%) fatal stroke from brain hemorrhage, all of which occurred during the procedure with no events occurring after discharge. In addition, two (0.6%) transient ischemic attacks and three (0.9%) reperfusion syndromes occurred, with the patients experiencing complete recovery. CONCLUSION: Carotid artery stent placement with use of the distal balloon protection system is feasible and safe, and the short-term outcomes appear to be favorable. Optimal application of proper technique is important.

Effectiveness of elective stenting of common carotid artery lesions in preventing stroke.

We report our experience with elective stenting of lesions only involving the origin and proximal common carotid arteries. In 37 patients (42 vessels), procedural success was 95% (40 of 42 vessels) with 2 minor strokes (4.70%) and no major strokes. Follow-up for a mean of 24 months showed 1 transient ischemic attack, 2 contralateral minor strokes, 1 cerebral hemorrhage associated with long-term warfarin therapy, and a 5.1% restenosis rate. This technique is an excellent alternative for treating proximal and ostial lesions of the common carotid artery.

Predictors of restenosis after successful carotid artery stenting.

This study was performed to determine the risk factors for restenosis after successful carotid stenting. Of 222 patients who underwent successful carotid stenting, 179 (81%) had a follow-up study (carotid ultrasound and/or angiogram). Restenosis rate was 6.7% (14 of 195) for vessels. By univariate analysis, restenosis rates were significantly different between men and women (4% vs 15.4%, p = 0.018) and age < or =75 versus >75 years (3.8% vs 16%, p = 0.013). By multivariate analysis, older age (odds ratio [OR] 1.107, p = 0.015), female sex (OR 3.519, p = 0.001), implantation of multiple stents (OR 2.363, p = 0.019), and postprocedural percent stenosis (OR 1.067, p = 0.054) were associated with increased incidence of restenosis.

Staged bilateral carotid stenting, an effective strategy in high-risk patients - insights from a prospective multicenter trial.

OBJECTIVE: To prospectively evaluate outcomes of high-risk patients undergoing bilateral carotid artery stenting (CAS). METHODS: A total of 747 patients at increased risk for carotid endarterectomy (CEA) were enrolled in a prospective registry at 47 US sites of the Boston Scientific EPI: A Carotid Stenting Trial for Risk Surgical Patients (BEACH) trial. Among them, 78 (10.4%) patients underwent contralateral CAS > 30 days after the primary CAS procedure. Patients were followed at 1, 6, and 12 months, and annually thereafter for 3 years. The primary endpoint was the cumulative incidence of non Q-wave myocardial infarction within 24 hours, periprocedural (

Carotid artery revascularization in high-surgical-risk patients using the Carotid WALLSTENT and FilterWire EX/EZ: 1-year outcomes in the BEACH Pivotal Group.

OBJECTIVES: The multicenter, single-arm BEACH (Boston Scientific EPI: A Carotid Stenting Trial for High-Risk Surgical Patients) evaluated outcomes in high-surgical-risk patients with carotid artery stenosis treated with the Carotid WALLSTENT plus FilterWire EX/EZ Emboli Protection System (Boston Scientific, Natick, Massachusetts). BACKGROUND: Carotid artery stent (CAS) placement offers a less invasive alternative for high-risk surgical carotid endarterectomy (CEA) patients. METHODS: The trial enrolled 480 pivotal patients who were candidates for carotid revascularization but considered high surgical risk due to pre-specified anatomic criteria and/or medical comorbidities. The primary end point (all stroke, death, or Q-wave myocardial infarction [MI] through 30 days; non-Q-wave MI through 24 h; and ipsilateral stroke or neurologic death through 1 year) was compared with a proportionally weighted objective performance criterion (OPC) of 12.6% for published surgical endarterectomy results in similar patients, plus a pre-specified noninferiority margin of 4%. RESULTS: Among pivotal patients, 41.2% were at high surgical risk due to comorbid risk factors, and 58.8% due to anatomic risk factors; 76.7% were asymptomatic with flow-limiting carotid stenosis >80%. At 1 year, the composite primary end point occurred in 8.9% (40 of 447), with a repeat revascularization rate of 4.7%. With an upper 95% confidence limit of 11.5% for the primary composite end point, the BEACH trial results met the pre-specified criteria for noninferiority relative to the calculated OPC plus noninferiority margin (16.6%) for historical surgical CEA outcomes in similar patients (p < 0.0001 for noninferiority). CONCLUSIONS: The BEACH trial results demonstrate that CAS with the WALLSTENT plus FilterWire embolic protection is non-inferior (equivalent or better than) to CEA at 1-year in high-surgical-risk patients.

Carotid stenting with distal protection in high surgical risk patients: the BEACH trial 30 day results.

BACKGROUND: The BEACH trial evaluated the outcomes of carotid artery stent placement with distal emboli protection, using the Carotid Wallstent and the FilterWire EX/EZ(TM), in patients at high surgical risk for carotid endarterectomy (CEA). METHODS: We enrolled 747 patients at high surgical risk for CEA due to prespecified anatomical criteria and/or medical comorbidities. The trial included both symptomatic (>50% carotid artery stenosis) as well as asymptomatic (>80% carotid artery stenosis) high surgical risk patients. Three groups of patients were included in the trial. The Roll-in (R) group (n = 189/747, [25%]) included up to nine patients per site for familiarization of the device and protocol; the Pivotal (P) group (n = 480/747, [65%]) was intended for presentation to the FDA for consideration of device approval; and a Bilateral (B) registry group (n = 78/747, [10%]) was included because of the need to treat patients with bilateral carotid artery disease. In the 480 Pivotal patients, anatomic criteria represented the most frequent high-risk surgical category for enrollment (58.8%), followed by prior CEA (34.2%), multivessel (>or=2) coronary artery disease (21.7%), and contralateral carotid occlusion (18.1%). RESULTS: The technical success rate for stent deployment and FilterWire EX/EZ deployment and retrieval was 98.2%. The mean postprocedure angiographic diameter stenosis in the Pivotal group was reduced to 10.8%, while the overall procedure success rate (<50% residual diameter stenosis) after stent deployment was 98%. The 30 day composite major adverse event (MAE) rate for the entire cohort of 747 patients (i.e. inclusive of all 3 groups) was 5.8% (all death = 1.5%, all stroke = 4.4%, and all myocardial infarction (MI) = 1.0%). In subgroup analysis, there was no significant difference in the MAE rate between the three groups (P = 5.8%, R = 6.9%, B = 2.6%, P = 0.42). CONCLUSION: The similarity in periprocedural event rates for the Pivotal and Roll-in groups suggests a flat learning curve for experienced operators using this carotid stent system. The similarity in event rates for the Bilateral group, when compared with the Roll-in and Pivotal groups, suggests that staged sequential treatment of bilateral stenoses may be performed at the same risk as for unilateral lesions. The 30-day safety of this stent and distal emboli protection system is encouraging and compares favorably with other carotid stent trials in high surgical risk patients.

Estrogen-eluting, phosphorylcholine-coated stent implantation is associated with reduced neointimal formation but no delay in vascular repair in a porcine coronary model.

Estrogen can inhibit intimal proliferation and accelerate endothelial regeneration after angioplasty. This suggests that estrogen may prevent in-stent restenosis. Unlike other therapies to prevent restenosis, estrogen may also not delay endothelial regrowth, thereby avoiding the risk of late stent thrombosis. The purpose of this work was to determine the effect of a 17beta-estradiol-eluting stent on neointimal formation in a porcine model. Each artery of six pigs was randomized to either a control, low-dose, or high-dose 17beta-estradiol-eluting stent. All animals were sacrificed at 30 days for histopathological analysis. There was a 40% reduction in intimal area in the high-dose stents compared with control stents (2.54 +/- 1.0 vs. 4.13 +/- 1.1 mm(2), for high dose vs. control, respectively; P < 0.05). There was complete endothelial regeneration at 30 days and similar inflammatory response to stenting on histopathology in all the stent groups. This is the first study to show that 17beta-estradiol-eluting stents are associated with reduced neointimal formation without affecting endothelial regeneration in the pig model of in-stent restenosis. Estrogen-coated stents may have a potential benefit in the prevention and treatment of in-stent restenosis.