Advances in stent technology for femoral artery lesions and use of stents forvenous pathology

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Anne LEJAY1,2,
Yannick GEORG1,2,
Elvira TARTA GLIA1,
Fabien THAVEAU1,2,
Philippe NICOLINI3,
Nabil CHAKFE1,2
1. Department of Vascular Surgery,
University Hospital of Strasbourg and University of Strasbourg, Strasbourg,
France.
2. European Research Group on Grafts used in Vascular Surgery (GEPROVAS),
Strasbourg, France.
3. Clinique du Parc, Lyon, France.

ABSTRACT

Endovascular surgery with femoral superficial artery stent implantation was first conducted over 20 years ago. However, the first experiments with steel stents were relatively disappointing. A notable advance was the development of nitinol stents, which led to an initial improvement in clinical outcomes, but a relatively high rate of fractures. A better understanding of the biomechanics of the superficial femoral artery and technological developments have led to a second generation of nitinol stents with improved flexibility, and thereby fewer fractures. The phenomenon of restenosis related to neointimal hyperplasia has also led to the development of new concepts in stents including: drug-eluting, biodegradable, and covered stents. These technologies are of use for treating the more complex lesions of the superficial femoral artery, but also extend the endovascular indications of stents to venous pathology, such as vein compression syndrome in the upper or lower deep veins with deep vein thrombosis, and postthrombotic syndrome of the lower legs.

INTRODUCTION

Peripheral arterial disease is a manifestation of systemic atherosclerosis and its prevalence increases with age. Remarkable technological advances in the past decade, along with patient preference, have shifted revascularization strategies from traditional open surgical approaches toward lower morbidity percutaneous endovascular treatments.1,2 Although the superficial femoral artery (SFA) is the artery most commonly affected by atherosclerosis, it has nevertheless many particularities compared with other arteries in the human body. Indeed, the SFA is the longest artery in the human body, and has two major points of flexion: hip and knee. During movement, the SFA is exposed to various stresses,3 which is a major reason for the high restenosis rate observed after angioplasty, with or without stenting.4 Better knowledge of the biomechanics of the SFA and technological developments have led to the introduction of new stents, with better results. These arterial endovascular techniques have also been applied to extrinsic compression of the deep veins, as well as for postthrombotic syndrome.

STENT EVOLUTION FOR SUPERFICIAL
FEMORAL ARTERY LESIONS

The first stent was developed by Hans Wallsten, a Swedish engineer, in Lausanne. It consisted of a self-expandable intravascular coil, first of metal wires, which were subsequently covered with a polyester fabric. The stent could be bare or covered with a silicone or polyurethane lining. Deployment tools were also designed and manufactured to allow percutaneous introduction and correct coil deployment. The first results were quite satisfactory: easy to implant in large vessels; perfect stability of the coil when deployed in the ascending aorta without major histological changes in the aortic wall; and progressive growth of the endothelial cell lining from both extremities, covering progressively the whole metallic or polyester mesh. After a year of extensive animal studies, the device became known as a stent rather than a coil, and clinical trials were carried out. Extravascular applications were also started in urology and the gastrointestinal tract with promising results, but the real market of stents was atherosclerotic vessels. At this time, the main issues with stents appeared in small vessels, as a result of acute occlusion of the vessel by early thrombosis on the foreign material, and late progressive narrowing of lumen size by in-stent tissue in-growth. The first studies with the Wallstent™ showed re-occlusion rates of up to 70% at 3 years in the SFA,5 and stenting indications were limited to residual stenosis or dissection.6,7

A major advance occurred with the introduction of nitinol stents. Nitinol is an alloy of nickel and titanium, with two essential properties: shape memory, and elasticity.8,9 The SIROCCO study compared a rapamycin-coated stent with a bare nitinol stent to combat in-stent restenosis in the SFA.10 The study demonstrated good efficacy of the uncoated stent in the control group, with comparable patency rates between groups. The SIROCCO II study also showed for the first time acceptable levels of in-stent restenosis with rates of 17.9% in the nitinol group, and 20.7% in the rapamycin-coated-stent group, a non-significant difference11. Since this accidental discovery, industry and the scientific community have heavily invested in the development of nitinol stents, and obtained acceptable patency rates: 75% and 66% for 1-year and 3-year primary patency, respectively, for stenosis, and 73% and 64% for 1-year and 3-year primary patency, respectively, for occlusion4. The first generation of nitinol stents presented a relatively high fracture rate, around 24% in SIROCCO II, leading to the development of a second generation of nitinol stents. The newer generation of nitinol stents demonstrated greater flexibility with lower fracture rates, and were produced in lengths of up to 20 cm. They not only improved outcomes compared with angioplasty alone, but could also treat longer and greater numbers of lesions, particularly in the context of critical limb ischemia.12

Drug-eluting stents were developed to prevent instent restenosis. Restenosis is mainly due to neointimal proliferation of smooth muscle cells. The use of various pharmacological methods to inhibit the proliferation of smooth muscle cells led to the concept of drug-eluting stent, which not only keep the artery open, but also act as a pharmacological platform. The stent is capable of delivering a pharmacological agent in situ, in contact with the arterial wall, and thus inhibiting restenosis at the initiation of the process. Drug-eluting stents combine three components: the pharmacological agent, the drug delivery system (usually a polymer), and the bare metal stent. Major meta-analyses of randomized controlled trials from interventional cardiology have shown that the use of drug-eluting stents for coronary artery disease has resulted in decreased in-stent restenosis and reintervention rates compared with bare metal stents.13-15

While the use of drug-eluting stents is well known in coronary pathology, it may be more complex in lower limb arteries. Indeed, peripheral lesions are often longer and more calcified than coronary lesions, and the biological response of peripheral arteries to the endovascular treatment appears to be different from coronary arteries. The SIROCCO investigators provided objective evidence of the safety and efficacy of drug eluting stents in patients with critical limb ischemia, but without a significant difference in terms of restenosis between drug-eluting stents and bare stents.10-11 The STRIDES trial (Superficial femoral artery TReatment with Drug-Eluting Stents)16 was a prospective, nonrandomized, single-arm, multicenter controlled trial designed to evaluate the safety and performance of an everolimus-eluting self-expandable stent, in above-knee femoropopliteal de novo or restenotic lesions up to 17 cm in length. The primary end point was in-stent restenosis in the superficial femoral artery at 6 months. Secondary end points included angiographic measurements of the change in vessel lumen diameter between time of stent placement and 12 months, restenosis at 12 months, as well as 5 years of clinical follow-up to track resolution of peripheral arterial disease symptoms, limb salvage, and patient survival. One hundred and four patients were enrolled in 11 European investigative centers. The patients had severe peripheral vascular disease with a mean lesion length of 9 ± 4.3 cm. Ninety-nine percent of patients were available for 12-month follow-up, including duplex imaging in 90% and angiography in 83%. Clinical improvement was achieved in 80% of patients. Primary patency (freedom from ≥50% instent restenosis) was 94% at 6 months, and 68% at 12 months. Radiographic examination of 122 implanted devices at 12 months revealed no evidence of stent fracture. The authors concluded that the everolimus-eluting self-expanding nitinol stent could be safely and successfully implanted in patients with severe peripheral arterial disease, with favorable outcomes and clinical improvements observed in the majority of patients. Neointimal hyperplasia appeared to be inhibited and patency enhanced during the first 6 months. The effect was not sustained, however, as primary patency decreased to 68% by 12 months. Further improvements in the performance of drug-eluting stents will require the development of nonthrombogenic absorbable polymeric coating matrices with suitable degradation profiles, and a low inflammatory tissue response during polymer degradation to allow for a quick and complete stent endothelialization.

Another notable development was the evolution of bio-absorbable stents. The history of absorbable stents dates back to the mid-1980s. Since then, a number of international research groups have evaluated absorbable stent designs, but most have only reached preclinical evaluation. Interest in the development of biodegradable stents is based on the idea of decreasing in-stent restenosis by limiting the time of implantation of a metallic material, foreign to the arterial wall.17 Although current highly successful stent technology is based on permanent metallic stent platforms, there is clinical consensus that stents are only required during the vascular healing period after stent implantation. Unlike permanent bare-metal stents and drug-eluting stents, which are both associated with long-term constrictive vascular remodeling, absorbable stents could be completely replaced by tissue, and may even allow positive vascular remodeling. Unlike permanent stents, a further advantage of absorbable stents is that they will not interfere with advanced imaging techniques (magnetic resonance imaging compatibility) and vascular surgery. However, the fact that absorbable stents cannot yet be found in clinical practice, and clinical testing is limited, is largely because of the inferior mechanical properties of degradable polymers compared with permanent metallic stent materials. Two main types of biodegradable stents are currently available: metal and polymer. As a result of their thickness and lack of radial force, biodegradable polymer stents are not good candidates for peripheral arterial disease. In fact, clinical experience with absorbable vascular stents is very limited and is insufficient to assess the efficacy and the safety of biodegradable stents in peripheral arterial disease. Major technical improvements will be necessary before biodegradable stents can be used with acceptable results.18,19

Covered stents were first used to treat vascular perforations, and to exclude aneurysms, but have subsequently been used for the prevention of in-stent restenosis. The aim is to prevent the vascular wall cells responsible for restenosis from proliferating through the mesh of the stent by covering the stent with a membrane.17 The first results obtained with polyethylene-terephthalate- covered stents were not very encouraging. Other results with polytetrafluoroethylene-covered stents were more satisfactory. The theoretical benefit of the expanded polytetrafluoroethylene-covered nitinol stent graft is that in-growth of tissue between the stent struts, which plagues SFA stents, is prevented. However, edge restenosis may not be avoided, and concerns about stent thrombosis must be addressed. A randomized prospective study evaluated 100 limbs in 86 patients with peripheral arterial disease due to stenosis or occlusion of the SFA.20 These patients had been treated by prosthetic femoro-popliteal bypass or angioplasty with insertion of a polyethylene-terephthalate- covered stent. The stent graft group demonstrated a primary patency of 72%, 63%, 63%, and 59% with a secondary patency of 83%, 74%, 74%, and 74% at 12, 24, 36, and 48 months, respectively. No difference was found between groups. The contoured edge heparin bond ViabahnTM endoprosthesis has been compared with nitinol stent placement in TASC II C and D femoro-popliteal lesions. Despite significant early failures, ViabahnTM endoprosthesis treatment may be durable in patients who do not have early failure, and ViabahnTM stent-graft assisted sub-intimal recanalization is an acceptable alternative to vein bypass in selected patients with severe SFA disease.21,22 However, potential disadvantages of using self-expanding endoprostheses include the sheath size needed for these large-caliber systems (≥ 7 or 8 Fr), the occlusion of side branches, a nonspecific systemic vascular wall reaction, and their high cost. Due to the relatively low radial force of the endoprostheses, particularly when used in recurrent stenoses and occlusions, it is important to create an adequate lumen to allow the prosthesis to be introduced and expanded. However, ViabahnTM endoprostheses up to 25 cm long are available in Europe and just recently the device diameter has been downsized to 6 Fr for 5 mm and 6 mm endoprostheses.

USE OF STENTS FOR VENOUS PATHOLOGY

Iliac vein compression syndrome is the symptomatic compression of the left common iliac vein between the right common iliac artery and the vertebrae.23 This compression may cause left lower extremity deep vein thrombosis or chronic symptoms of venous hypertension without thrombosis such as edema, leg heaviness, varicose veins, skin pigmentation, and ulceration. Iliocaval obstructive disease was traditionally treated by surgical techniques that could be very invasive. Unlike obstructive arterial lesions, where endovascular procedures are now part of routine therapy, stenosis or occlusions of large caliber veins are not currently treated by endovascular surgery. The poor performance of many surgical techniques for the treatment of iliocaval obstructive disease led to a disinterest in surgery for the treatment of these lesions that prevailed until 2000. More recently, endovascular techniques have transformed the treatment of both acute and chronic iliocaval obstructive lesions. Balloon dilation alone or completed by stenting of the venous stenosis is used in the treatment of acute thrombosis in addition to iliac thrombolytic treatment or surgical thrombectomy. Stents are also now used in the treatment of primitive (Cockett or May-Thurner syndrome) or secondary (post-thrombotic) iliac stenosis or occlusion.24,25 Apart from neoplasic obstructions, endovascular treatment for iliac vein compression syndrome has become, in little more than 10 years, the technique of choice and represents a new and minimally invasive way to treat occlusive iliocaval lesions.

Venous endovascular surgery requires the use of guide wires. In patients with acute deep vein thrombosis (<15 days), a venous thrombectomy combined with the creation of an arteriovenous fistula can provide good immediate and long-term results.26 However, when thrombolysis is induced via multiperforated catheters, residual stenosis lesions are frequent and are a cause of early rethrombosis. Mickley et al showed that residual stenosis led to rethrombosis in 73% of cases, while only in 13% after stenting.27 Rates of primary and secondary patency in the long term (60 months) were 72% and 88%, respectively. Thus, angioplasty combined with stenting should be systematically performed during a venous thrombectomy in all patients with obstructive lesions.

Chronic lesions have a considerable impact on patients’ quality of life and are very disabling. Medical treatment, mainly venous elastic restraint, is not always sufficient to enable patients to lead normal lives. Several teams have reported good results with patency rates of stented segments of around 90% at 24 months. Raju et al presented results for 304 limbs with iliac vein compression syndrome and reported a stent patency rate at 24 months of 90%.28 The median degree of swelling and pain were significantly reduced, and the ulcer healing rate was 62%. Hartung et al reported similar mid-term results after endovascular treatment.29 The stent patency rate at 36 months was 90%, and thrombotic occlusion occurred in 5% of limbs. Stents for stenosis of the left iliac vein can therefore enhance treatment of long-term chronic swelling and ulcers of the lower extremities, but can also prevent recurrence of secondary complications.30 In fact, iliac vein stent placement is a safe and effective method for improving the patient’s quality of life. The choice of the stent and its positioning are crucial. Stents must be self-expanding, because of the crushing risk of balloon expandable stents. Iliac stents must be at least 60 mm long and 16 mm in diameter in order to extend past both sides of the lesion and to prevent their migration. Raju et al showed that stents should be placed across the iliocava confluence and that this positioning does not induce a risk of right common iliac vein thrombosis. Compared with the experience of placing stents in other areas, such as the femoral artery and sub-clavian vein, the long-term patency of an iliac vein stent is considerably higher. Possible reasons are the relatively immobile position of the pelvic stents compared with the freely mobile femoral artery or sub-clavian vein, as well as the lack of compression, contraction, torsion and flexion from bony structures or muscular motion. In addition, the length of the stenosis is much shorter than in a femoral artery, which is associated with arteriosclerosis.

Upper extremity deep vein thrombosis occurs frequently and can cause considerable morbidity, including pulmonary embolism in one-third of cases.31 Thrombosis is most often observed in the axillary or sub-clavian veins. Primary deep vein thrombosis is rare, and is known as effort thrombosis (Paget-Schroetter syndrome) or idiopathic thrombosis. Idiopathic thrombosis may by suggestive of cancer (lung cancer or lymphoma). The prevalence of hypercoagulability in these patients is variable, but other risk factors such as a personal or family history of deep vein thrombosis should be sought. Secondary deep vein thrombosis is more frequent and mostly observed in patients with a central catheter, pacemaker, or cancer. Axillary or sub-clavian vein thrombosis may be asymptomatic, but patients may complain of discomfort in the shoulder or neck, swelling of the arm, dizziness or dyspnea in case of obstruction of the superior vena cava.

The traditional method of treating malignant central venous obstruction is radiotherapy and chemotherapy, which is effective in 90% of cases; surgery is rarely indicated. A clinical response to chemotherapy and radiotherapy is seen after one week, but there is a 20% recurrence rate, even after the use of the total permissible dose of radiation. The high recurrence rate is due to progression of disease, post-radiation fibrosis, or complicating thrombosis. Due to the relatively long latent period between medical treatment and clinical response and the high rate of recurrence, endovascular management with venous stenting should be initiated early and may be considered a first line intervention. Balloon veinoplasty with stent placement provides nearly instantaneous symptomatic relief with a low risk of side effects and high long-term patency. Nagata et al reported primary and secondary patency rates of 88% and 95%, respectively, for malignant superior vena cava syndrome.32 Stenting of benign stenosis or obstruction is undertaken less frequently than stenting in the setting of malignancy, although the number of cases is increasing. Obstruction in the setting of catheter-related stenosis or chronic thrombosis may be improved or relieved by removal of the catheter, but this may not be an option in patients with tenuous venous access or catheter dependence. Balloon angioplasty is the mainstay of treatment, and stent placement is reserved for patients in whom angioplasty has failed due to elastic recoil or restenosis of the vessel. Benign obstructions are frequently difficult to treat successfully with venoplasty alone and may require multiple reinterventions and eventual stent placement to maintain venous patency. Studies have shown a 24-month primary patency of about 90%, with a 16% reintervention rate.33-35 Data for upper extremity deep vein stenting are lacking.

CONCLUSION

The advent of new stent technology, with its potential to overcome in-stent restenosis as the major limitation of conventional bare metal stents, has had a very large influence on clinical practice in vascular intervention. However, initial enthusiasm about drug-eluting stents has been replaced by discussion about their risks in terms of incomplete endothelialization, as well as hypersensitivity reactions to the polymer coating. Clinically, these potential complications following drug eluting stent implantation are observed as sub-acute or late stent thrombosis. Whether or not thrombosis is more frequent with drug-eluting stents than with bare metal stents is still the subject of scientific debate. However, it is clear that there is a great demand for improved and possibly degradable drug-eluting stent coatings with higher biocompatibility and improved pharmacological action compared with first generation drug-eluting stents. Novel approaches currently being pursued encompass the use of polymer-free or biocompatible, absorbable, polymeric, drug-eluting stent coatings together with the promotion of vascular healing by the application of alternative active agents. Ultimately, fully absorbable stents or absorbable drug-eluting stents based on degradable polymers may replace permanent stents due to their inherent advantages over permanent implants, and their options for bulk incorporation of drugs. Although the feasibility of absorbable polymer stents has already been established, important issues, such as long-term fatigue resistance and absorption behavior until complete disappearance, will have to be addressed in future studies before they enter routine clinical use. Endovascular treatment of peripheral arterial disease continues to evolve, with expectations of improvements in safety and long-term durability with newer technologies ranging from local drug delivery to bioabsorbable stents. Percutaneous procedures will continue to replace open surgery as well as venous open surgery, especially for iliac vein compression syndrome.



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